Search

[Display omitted] Chemo-immunotherapy, in which chemotherapeutic drugs activate immune system to suppress tumor growth and metastases, has great potential for clinical application. However, insufficient immunogenic cell death and serious side effects caused by tumor multidrug resistance and non-specific drug distribution, as well as inadequate and dysfunctional immune cells, greatly impair the effectiveness of chemo-immunotherapy. Herein, taking advantage of the functional diversity and structural programmability of nucleic acids, a DNA-based bioorthogonal nanoagonist is constructed to initiate and augment immune responses for robust chemo-immunotherapy. Benefiting from polyvalent targeting and template effects of DNA, the tailor-made nanoagonist shows prior bioorthogonal catalytic performance. Chemotherapeutic drug is bioorthogonally synthesized in situ under the catalysis of the nanoagonist, maximizing immunogenic cell death and minimizing systemic toxicity. The large amount of antigen and damage-associated molecular patterns released from dying tumor cells effectively initiates antitumor immunity. Meanwhile, the integration of high density of immunologic adjuvant can more effectively stimulate immune cells. The combination of bioorthogonal catalytic drug synthesis and immunostimulatory effect of DNA adjuvant not only destroys local primary tumors, but also eliminates distal metastasis. Moreover, the nanoagonist triggered the immune memory effect. The work extends the application of bioorthogonal chemistry to immunotherapy and provides a safe and powerful strategy for cancer chemo-immunotherapy. [ABSTRACT FROM AUTHOR]

[Display omitted] • High ENOX2 expression is associated with immune excluded/deserted phenotypes in NPC. • ENOX2 inhibitor, idronoxil enhances CD8+ memory T -cell immunity in response to chemotherapy. • Combined treatment with idronoxil and cisplatin enhances tumor response in humanized mice model. • Combined treatment increases CD8+ T -cell expansion with cytolytic effector memory (Tem) feature. • T -cell infiltrates and tumor-associated ENOX2 have predictive value for anti-tumor response. The immunosuppressive tumor microenvironment is a major barrier for chemotherapy. Different chemosensitization approaches to reinstate immunological surveillance for cancers that are immune quiescent at the outset, have thus been devised. Cancer-specific ENOX2 expression is correlated with abnormal cell growth and has been proposed as a cellular target for anti-cancer activity. However, the potential effects of ENOX2 on the interaction between immune system and tumor cells remain elusive. To understand the mechanisms by which tumor-intrinsic ENOX2-mediated alterations in anti-tumor activity of T -cells and response to chemotherapy. In situ multiplexed immunohistochemistry with single cell and bulk RNA sequencing data from nasopharyngeal carcinoma (NPC) human tissues were used to define tumor phenotypes. Two NPC cell lines, with distinct ENOX2 expression, were used in a co-culture platform to study tumor-immune interactions between cancer cells/spheroids and T -cells. The effect of cisplatin treatment with ENOX2 inhibition by idronoxil (IDX) were tested in vitro and in vivo. Multi-parametric flow cytometry was used to characterize T -cell infiltrates in an NPC tumor humanized mouse model treated with combined treatment. NPC predominantly displayed an immune-excluded profile. This "cold-phenotype" was shown to exhibit higher ENOX2 expression and was associate with poorer progression-free survival (PFS). The therapeutic combination of IDX with cisplatin was effective in promoting CD8+ effector memory T cell (Tem) differentiation and mobilization. This Tem signature was highly cytotoxic, with Tem-mediated preferential lysis of higher ENOX2-expressing NPC cells. A combination-treated humanized mouse model showing dramatic shrinkage in tumors, were intra-tumoral Tem-enriched. Tumor-intrinsic ENOX2 expression is associated with tumor phenotype and PFS in NPC. Targeting ENOX2 with IDX and cisplatin impose qualitative control of T -cell response by preferentially increasing immune cells infiltration, Tem differentiation and tumor suppression. We suggest that ENOX2 inhibition may be a promising therapeutic strategy to enhance the effects of chemotherapy. [ABSTRACT FROM AUTHOR]

• Single-dose CoVac-1 induces long-lasting T cell responses in 100% of participants. • Long-term follow-up shows good tolerability and no immune-related side effects. • Magnitude of T cell responses correlates with severity of injection site reactions. • Most CoVac-1-induced peptide-specific immunoglobulin G antibodies peaked at month 3. • Very low SARS-CoV-2 infection rate (8.3 %) in the study population. T cell immunity is key for the control of viral infections including SARS-CoV-2, in particular with regard to immune memory and protection against arising genetic variants. We recently evaluated a peptide-based SARS-CoV-2 T cell activator termed CoVac-1 in a first-in-human trial in healthy adults. Here, we report on long-term safety and efficacy data of CoVac-1 until month 12. CoVac-1 is well tolerated without long-term immune-related side effects and induces long-lasting anti-viral T cell responses in 100% of study participants, with potent expandability of clusters of differentiation (CD4+) and CD8+ T cells targeting multiple different CoVac-1 T cell epitopes. T cell responses were associated with stronger injection site reaction. Beyond induction of T cell immunity, 89% of subjects developed CoVac-1-specific immunoglobulin G antibodies which associated with the intensity of the T cell response, indicating that CoVac-1-specific CD4+ T cells support the induction of B-cell responses. Vaccination with approved COVID-19 vaccines boosted CoVac-1-specific T cell responses. Overall, a low SARS-CoV-2 infection rate (8.3%) was observed. Together, a single application of CoVac-1 elicits long-lived and broad SARS-CoV-2-specific T cell immunity, which further supports the current evaluation of our T cell activator in patients with congenital or acquired B-cell defects. [ABSTRACT FROM AUTHOR]

Bacillus Calmette-Guérin (BCG) vaccination induces a type of immune memory known as "trained immunity", characterized by the immunometabolic and epigenetic changes in innate immune cells. However, the molecular mechanism underlying the strategies for inducing and/or boosting trained immunity in alveolar macrophages remains unknown. Here, we found that mucosal vaccination with the recombinant strain rBCGPPE27 significantly augmented the trained immune response in mice, facilitating a superior protective response against Mycobacterium tuberculosis and non-related bacterial reinfection in mice when compared to BCG. Mucosal immunization with rBCGPPE27 enhanced innate cytokine production by alveolar macrophages associated with promoted glycolytic metabolism, typical of trained immunity. Deficiency of the mammalian target of rapamycin complex 2 and hexokinase 1 abolished the immunometabolic and epigenetic rewiring in mouse alveolar macrophages after mucosal rBCGPPE27 vaccination. Most noteworthy, utilizing rBCGPPE27's higher-up trained effects: The single mucosal immunization with rBCGPPE27-adjuvanted coronavirus disease (CoV-2) vaccine raised the rapid development of virus-specific immunoglobulin G antibodies, boosted pseudovirus neutralizing antibodies, and augmented T helper type 1-biased cytokine release by vaccine-specific T cells, compared to BCG/CoV-2 vaccine. These findings revealed that mucosal recombinant BCG vaccine induces lung-resident memory macrophages and enhances trained immunity via reprogramming mTORC2- and HK-1-mediated aerobic glycolysis, providing new vaccine strategies for improving tuberculosis (TB) or coronavirus variant vaccinations, and targeting innate immunity via mucosal surfaces. [ABSTRACT FROM AUTHOR]

• Living conditions affect the exposure to SARS-CoV-2 in vaccinated individuals. • T cell reactivity to SARS-CoV-2 wanes over time. • Reinfection of dormitory dwellers occurred as Omicron spread. • T cell reactivity greatly increased the protection from reinfection to SARS-CoV-2. • Elevated SARS-CoV-2 titers did not confer complete immunity. We investigated the reinfection rate of vaccinated or convalescent immunized SARS-CoV-2 in 952 expatriate workers with SARS-CoV-2 serological antibody (Ab) patterns and surrogate T cell memory at recruitment and follow-up. Trimeric spike, nucleocapsid, and neutralizing Abs were measured, along with a T cell stimulation assay, targeting SARS-CoV-2 memory in clusters of differentiation (CD) 4+ and CD8+ T cells. The subjects were then followed up for reinfection for up to 6 months. The seroprevalence positivity at enrollment was greater than 99%. The T cell reactivity in this population was 38.2%. Of the 149 (15.9%) participants that were reinfected during the follow-up period (74.3%) had nonreactive T cells at enrollment. Those who had greater than 100 binding Ab units/ml increase from the median concentration of antispike immunoglobulin G Abs had a 6% reduction in the risk of infection. Those who were below the median concentration had a 78% greater risk of infection. Significant immune protection from reinfection was observed in those who retained T cell activation memory. Additional protection was observed when the antispike was greater than the median value. [ABSTRACT FROM AUTHOR]

The immune system produces a diverse collection of anti-glycan antibodies that are critical for host defense. At present, however, we know very little about the binding properties, origins, and sequences of these antibodies because of a lack of access to a variety of defined individual antibodies. To address this challenge, we used a glycan microarray with over 800 different components to screen a panel of 516 human monoclonal antibodies that had been randomly cloned from different B-cell subsets originating from healthy human subjects. We obtained 26 antiglycan antibodies, most of which bound microbial carbohydrates. The majority of the antiglycan antibodies identified in the screen displayed selective binding for specific glycan motifs on our array and lacked poly-reactivity. We found that antiglycan antibodies were about twice as likely than expected to originate from IgG+ memory B cells, whereas none were isolated from naïve, early emigrant, or immature B cells. Therefore, our results indicate that certain B-cell subsets in our panel are enriched in antiglycan antibodies, and IgG+ memory B cells may be a promising source of such antibodies. Furthermore, some of the newly identified antibodies bound glycans for which there are no reported monoclonal antibodies available, and these may be useful as research tools, diagnostics, or therapeutic agents. Overall, the results provide insight into the types and properties of antiglycan antibodies produced by the human immune system and a framework for the identification of novel antiglycan antibodies in the future. [ABSTRACT FROM AUTHOR]

• Moderate and severe/critical groups had high inflammation at presentation. • Inflammation did not normalize for the severe/critical at 2 weeks. • Mild and moderate groups had good T and B memory responses at 2 weeks. • Severe/critical group had an exhausted immune response at 2 weeks. • By 24 weeks, severe/critical group had good memory B and T cell responses. There are limited data on short- versus long-term changes in adaptive immune response across different COVID-19 disease severity groups. A multicenter prospective study of 140 adult patients with COVID-19 (a total of 325 samples) were analyzed for inflammatory markers and lymphocyte subsets at presentation, week 2, and week 24. Inflammatory markers at presentation were higher in the critical/severe than in moderate and mild groups. A predominance of memory B cell response in the mild and moderate group was noted by week 2. In contrast, the immune system in the severe/critical group was dysfunctional, with expansion of exhausted CD8+ T cells and atypical memory B cells. By 24 weeks, there was a possible trend of normalization. There was substantial difference in the degree of inflammation and distribution of different B and T cell subsets in the different disease severity groups. Despite the initial dysfunctional immune response in the severe/critical group, a comparable memory B and CD8+ T cell responses to the mild group was achieved at 24 weeks. [ABSTRACT FROM AUTHOR]

• A novel cationic COF material with good gene loading ability is designed. • The first implementation of COF itself achieved good gene silencing effects. • Create preformed gene carriers rather than unpredictable morphology and instability. • Effectively silenced PD-L1 and activated a powerful immune memory effect. • Present innovative applications of COF in the biomedical realm. Numerous studies have established the promise of combining phototherapy and gene therapy. However, there are persistent obstacles hindering the full optimization of this combined therapeutic approach, such as the maximum development of photosensitizers and the construction of high-performance gene carriers. The LEGO stacking characteristics of COFs have brought infinite imagination to the construction of delivery systems, allowing for the design of responsive nano castles based on different application scenarios. Here, we have constructed a novel cationic multifunctional nano COF nucleic acid delivery system based on photosensitizer and cationic monomers. The long-range ordered structure of COF effectively regulates the spatial distribution of photosensitizer, thereby preserving their phototherapy efficacy. Simultaneously, the inherent cationic porous nanostructure equips COF with exceptional capabilities for delivering nucleic acids. This integrated multifunctional nano delivery system significantly enhances the combined efficacy of phototherapy and gene therapy. The phototherapy capacity of COF enables precise tumor elimination in a spatiotemporal manner, inducing robust ICD and activating immune cells at the tumor site. Furthermore, loaded siPD-L1 significantly enhances immune cell recognition and killing of tumor cells, effectively shielding mice from re-invasion and tumor metastasis. The development of multifunctional nanomedicine based on COF provides new ideas for efficient tumor combination therapy. [ABSTRACT FROM AUTHOR]

• High tyrosine-rich protein statherin is integrated onto the surface of OMVs. • The construction of a radionuclide labeling vector based on engineered OMVs. • The engineered OMVs enhanced radio-immunotherapy. Radioisotope therapy (RIT) is one of clinical treatment for tumors, which can not only directly kill tumor cells, but also enhance anti-tumor immune response by inducing tumor cell immunogenic cell death (ICD). However, significant challenges for RIT are the low radiolabeling efficiency, as well as tumor targeting issues. Bacterial outer membrane vesicles (OMVs), which are natural nano-vesicles secreted by Gram-negative bacteria, are now garnering significant attention in cancer therapy due to their tumor-targeting and immunotherapeutic potential. Herein, we construct an engineering delivery platform based on OMVs to achieve efficient labeling of radioactive iodine and improve radio-immunotherapy (131I-STATH-OMV-PEG). Firstly, high tyrosine-rich protein statherin (STATH) is integrated onto the surface of OMVs (STATH-OMV) through bioengineered technology. The obtained STATH-OMV is coated with polyethylene glycol (PEG) and then labeled with radionuclide iodine-131 (131I-STATH-OMV-PEG), which exhibit excellent radiolabeling efficiency due to the integration of STATH. More importantly, 131I-STATH-OMV-PEG could also boost DC maturation and produce anti-tumor cytokines, thereby enhancing the systemic anti-tumor immune response induced by RIT. Additionally, 131I-STATH-OMV-PEG could inhibit orthotopic colon cancer, induce systemic immune memory effect and prevent tumor invasion. In summary, this study proposes an OMV-centered RIT delivery system that ensures proficient labeling of 131I, thereby amplifying the therapeutic effect of RIT and opening up a promising approach for tumor radio-immunotherapy. [ABSTRACT FROM AUTHOR]

Penicilazaphilone C (PAC) is hypothesized to potentially serve as a therapeutic treatment for allergic airway inflammation by inhibiting the NLRP3 inflammasome and reducing oxidative stress. An allergic asthma model was induced in female BALB/c mice of the OVA, OVA+PAC, OVA+PAC+LPS, and OVA+Dex groups by sensitizing and subsequently challenging them with OVA. The OVA+PAC and Normal+PAC groups were treated with PAC, while the OVA+PAC+LPS group also received LPS. The OVA+Dex group was given dexamethasone (Dex). Samples of serum, bronchoalveolar lavage fluid (BALF), and lung tissue were collected for histological and cytological analysis. Allergic mice treated with PAC or Dex showed inhibited inflammation and mucus production in the lungs. There was a decrease in the number of inflammatory cells in the BALF, lower levels of inflammatory cytokines in the serum and BALF, and a reduction in the protein expression of NLRP3, ASC, cleaved caspase-1, IL-1β, activated gasdermin D, MPO, Ly6G, and ICAM-1. Additionally, oxidative stress was reduced, as shown by a decrease in MDA and DCF, but an increase in SOD and GSH. Treatment with PAC also resulted in a decrease in pulmonary memory CD4+ T cells and an increase in regulatory T cells. However, the positive effects seen in the PAC-treated mice were reversed when the NLRP3 inflammasome was activated by LPS, almost returning to the levels of the Sham-treated mice. PAC acts in a similar way to anti-allergic inflammation as Dex, suggesting it may be a viable therapeutic option for managing allergic asthma inflammation. [Display omitted] • Penicilazaphilone C (PAC) demonstrates a similar ability to dexamethasone (Dex) in inhibiting allergic airway inflammation. • PAC modulates the airway immune microenvironment in a similar way to Dex. • PAC decreases airway inflammation and alters the airway immune microenvironment by inhibiting the NLRP3 inflammasome. • Modulating the lung microenvironment by inhibiting the NLRP3 inflammasome may be a potential strategy for treating asthma. [ABSTRACT FROM AUTHOR]

Advanced cholangiocarcinoma (CCA) presents a clinical challenge due to limited treatment options, necessitating exploration of innovative therapeutic approaches. Bispecific T cell engager (BTE)-armed T cell therapy shows promise in hematological and solid malignancies, offering potential advantages in safety over continuous BTE infusion. In this context, we developed a novel BTE, targeting CD3 on T cells and integrin αvβ6, an antigen elevated in various epithelial malignancies, on cancer cells. The novel BTE was generated by fusing an integrin αvβ6-binding peptide (A20) to an anti-CD3 (OKT3) single-chain variable fragment (scFv) through a G 4 S peptide linker (A20/αCD3 BTE). T cells were then armed with A20/αCD3 BTE (A20/αCD3-armed T cells) and assessed for antitumor activity. Our results highlight the specific binding of A20/αCD3 BTE to CD3 on T cells and integrin αvβ6 on target cells, effectively redirecting T cells towards these targets. After co-culture, A20/αCD3-armed T cells exhibited significantly heightened cytotoxicity against integrin αvβ6-expressing target cells compared to unarmed T cells in both KKU-213A cells and A375.β6 cells. Moreover, in a five-day co-culture, A20/αCD3-armed T cells demonstrated superior cytotoxicity against KKU-213A spheroids compared to unarmed T cells. Importantly, A20/αCD3-armed T cells exhibited an increased proportion of the effector memory T cell (Tem) subset, upregulation of T cell activation markers, enhanced T cell proliferation, and increased cytolytic molecule/cytokine production, when compared to unarmed T cells in an integrin αvβ6-dependent manner. These findings support the potential of A20/αCD3-armed T cells as a novel therapeutic approach for integrin αvβ6-expressing cancers. [Display omitted] • A20/αCD3 BTE targets both CD3 on T cells and integrin αvβ6 on cancer cells. • A20/αCD3-armed T cells exhibit higher antitumor activity compared to unarmed T cells. • A20/αCD3 BTE enhances T cell activation, proliferation, and cytokine secretion. [ABSTRACT FROM AUTHOR]

The complex of B- and T-lymphocyte attenuator (BTLA) and herpes virus entry mediator (HVEM) plays a critical role in immune regulation and has emerged as a promising therapeutic target for cancer treatment. In this study, we investigated the potential of the peptide inhibitor HVEM(14-39) to restore peripheral T cell activity in patients with advanced melanoma. In these patients, CD8+ T cells downregulated BTLA expression and increased HVEM expression upon activation. The addition of HVEM(14-39) reduced the percentage of BTLA+ CD8+ T cells and increased the subpopulation of HVEM+ CD8+ T cells. Additionally, HVEM(14-39) enhanced T cell activation, proliferation, and the shift toward effector memory T cell subpopulations. Finally, this peptide affected the proliferation rate and late apoptosis of melanoma cell line in co-culture with T cells. These findings suggest that HVEM(14-39) can overcome T cell exhaustion and improve antitumor responses. Peptide-based immunotherapy targeting the BTLA-HVEM complex offers a promising alternative to monoclonal antibody-based therapies, with the potential for fewer side effects and higher treatment efficacy. [Display omitted] • Targeting the BTLA/HVEM complex improves function of T cells in melanoma patients. • Peptide inhibitor HVEM(14−39) regains T-cell activation potential. • HVEM(14−39) may overcome T-cell exhaustion in cancer patients. • Peptide drugs as a promising solution for cancer immunotherapy. • HVEM(14−39) increases the proliferation of T-cell population in melanoma patients. [ABSTRACT FROM AUTHOR]

Chronic subdural hematoma (CSDH) is a prevalent form of intracranial haemorrhage encountered in neurosurgical practice, and its incidence has notably risen in recent years. Currently, there is a lack of studies that have comprehensively classified the cells present in hematomas removed during surgery, and their correlation with CSDH recurrence remains elusive. This study aims to analyse the subcellular populations and occupancy levels within peripheral blood. This study analyses the subcellular populations and occupancy levels within peripheral blood and postoperatively removed hematomas by single-cell sequencing and attempts to analyse the effect of different cell occupancies within peripheral blood and intraoperatively removed hematomas on CSDH. The single-cell sequencing results showed that the cells were classified into 25 clusters by differential gene and UMAP dimensionality reduction clustering analyses and further classified into 17 significant cell populations by cell markers: pDCs, CD8 T cells, CD4 T cells, MigDCs, cDC2s, cDC1s, plasma cells, neutrophils, naive B cells, NK cells, memory B cells, M2 macrophages, CD8 Teffs, CD8 MAIT cells, CD4 Tregs, CD19 B cells, and monocytes. Further research showed that the presence of more cDC2 and M2 macrophages recruited at the focal site in patients with CSDH and the upregulation of the level of T-cell occupancy may be a red flag for further brain damage. ROS, a marker of oxidative stress, was significantly upregulated in cDC2 cells and may mediate the functioning of transcription proteins of inflammatory factors, such as NFκB, which induced T cells' activation. Moreover, cDC2 may regulate M2 macrophage immune infiltration and anti-inflammatory activity by secreting IL1β and binding to M2 macrophage IL1R protein. The detailed classification of cells in the peripheral blood and hematoma site of CSDH patients helps us to understand the mechanism of CSDH generation and the reduction in the probability of recurrence by regulating the ratio of cell subpopulations. • cDC2, M2 macrophage enrichment linked to brain damage. • ROS upregulation in cDC2 may implicate T-cell activation. • cDC2-M2 interaction suggests new CSDH therapies. [ABSTRACT FROM AUTHOR]

A growing body of experimental and clinical evidence has implicated gut microbiota in the onset and course of rheumatoid arthritis (RA). The imbalance of intestinal flora in RA patients may lead to abnormal expression of immune cells and related cytokines. Conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) and conventional synthetic disease-modifying antirheumatic drugs combined with biological disease-modifying antirheumatic drugs (csDMARDs + bDMARDs) are widely used to treat RA, but the characteristics of gut microbiota before and after treatment and their relationship with memory Tfh/B cells and cytokines remain unclear. Stool samples were collected from 50 RA patients and 25 healthy controls (HCs) for 16SrRNA gene sequencing. We examined the proportion of lymphocyte subsets in healthy controls and RA patients. Enzyme linked immunosorbent assay (ELISA) was used to detect the levels of related cytokines in serum. The α and β diversity of intestinal flora, and the correlation between intestinal flora and clinical indicators, lymphocyte subsets, cytokines were analyzed. At the genus level, Ruminococcaceae_Ruminococcus was decreased in the csDMARDs and csDMARDs + bDMARDs treatment group, whereas Faecalibacterium was reduced in the csDMARDs treatment group, compared to untreated group. CD4+CD45RO+CCR7+CXCR5+central memory Tfh cells and CD4+CD45RO+CCR7-CXCR5+effector memory Tfh cells were significantly lower in the csDMARDs + bDMARDs treatment group than in untreated group. CD19+CD27+IgD+pre-switched memory B cells were higher in the csDMARDs and csDMARDs + bDMARDs treatment groups, whereas CD19+CD27+IgD-switched memory B cells were significantly lower than in untreated group. Ruminococcaceae_Ruminococcus was negatively correlated with CD19+CD27+IgD+ pre-switched memory B cells but positively correlated with CD4+CD45RO+CCR7-CXCR5+effector memory Tfh and CD19+CD27+IgD-switched memory B cells in patients with RA treated with DMARDs. The gut microbiota, memory Tfh cells, memory B cells, and cytokines of patients with RA changed significantly under different treatment regimens and had certain correlations with the clinical indicators of RA. [ABSTRACT FROM AUTHOR]

It is well-established that the reduced Memory B cells (MBCs) play an important role in the pathogenesis of ulcerative colitis (UC), rendering them a potential therapeutic target for UC intervention. Astragalus polysaccharide (APS), a primary active constituent derived from the classic traditional Chinese medicine Astragalus membranaceus (AM), has been used for centuries in the treatment of UC in both human and animal subjects due to its renowned immunomodulatory properties. However, it is unknown whether APS can regulate MBCs to alleviate experimental colitis. In the present investigation, the murine colitis was successfully induced using dextran sulphate sodium (DSS) and subsequently treated with APS for a duration of 7 days. APS exhibited significant efficacy in reducing the disease activity index (DAI), colonic weight index, the index of colonic weight/colonic length. Furthermore, APS mitigated colonic pathological injuries, restored the colonic length, elevated the immunoglobulin A (IgA), transforming growth factor-β1 (TGF-β1) and interleukin (IL)-10 levels, while concurrently suppressing IgG, IgM, IL-6, tumor necrosis factor alpha (TNF-α) levels. Crucially, the quantities of MBCs, IgA+MBCs and forkhead box P3 (Foxp3+) MBCs were notably increased along with a concurrent decrease in IgG1+MBCs, IG2a+MBCs, IgG2b+MBCs after APS administration in colitis mice. Additionally, the Mitotracker red expressions of MBCs and their subgroups demonstrated a significantly up-regulation. Meanwhile, the transcriptomics analysis identified mitochondrial metabolism as the predominant and pivotal mechanism underlying APS-mediated mitigation of DSS-induced colitis. Key differentially expressed genes, including B-cell linker (BLNK), aldehyde dehydrogenase 1A1 (ALDH1A1), B-cell lymphoma 6 (BCL-6), B-lymphocyte-induced maturation protein 1 (Blimp-1), paired box gene 5 (PAX5), purinergic 2 × 7 receptor (P2X7R), B Cell activation factor (BAFF), B Cell activation factor receptor (BAFFR), CD40, nuclear factor kappa-B (NF-κB), IL-6 and so on were implicated in this process. These mRNA expressions were validated through quantitative polymerase chain reaction (qPCR) and immunohistochemistry. These findings revealed that APS effectively restored MBCs and their balance to ameliorate DSS-induced colitis, which was potentially realized via promoting mitochondrial metabolism to maintain MBCs activation. [Display omitted] • APS ameliorated the DSS-induced Colitis in mice. • APS regulated memory B cells and balance in UC mice. • APS promoted mitochondrial metabolism to maintain memory B cells activation in UC mice. [ABSTRACT FROM AUTHOR]

Zhen-Wu-Tang (ZWT), a conventional herbal mixture, has been recommended for treating lupus nephritis (LN) in clinic. However, its mechanisms of action remain unknown. Here we aimed to define the immunological mechanisms underlying the effects of ZWT on LN and to determine whether it affects renal tissue-resident memory T (T RM) cells. Murine LN was induced by a single injection of pristane, while in vitro T RM cells differentiated with IL-15/TGF-β. We found that ZWT or mycophenolate mofetil treatment significantly ameliorated kidney injury in LN mice by decreasing 24-h urine protein, Scr and anti-dsDNA Ab. ZWT also improved renal pathology and decreased IgG and C3 depositions. In addition, ZWT down-regulated renal Desmin expression. Moreover, it lowered the numbers of CD8+ T RM cells in kidney of mice with LN while decreasing their expression of TNF-α and IFN-γ. Consistent with in vivo results, ZWT-containing serum inhibited T RM cell differentiation induced by IL-15/TGF-β in vitro. Mechanistically, it suppressed phosphorylation of STAT3 and CD122 （IL2/IL-15Rβ）expression in CD8+ T RM cells. Importantly, ZWT reduced the number of total F4/80+CD11b+ and CD86+, but not CD206+, macrophages in the kidney of LN mice. Interestingly, ZWT suppressed IL-15 protein expression in macrophages in vivo and in vitro. Thus, we have provided the first evidence that ZWT decoction can be used to improve the outcome of LN by reducing CD8+ T RM cells via inhibition of IL-15/IL-15R /STAT3 signaling. [Display omitted] • Zhen-Wu-Tang (ZWT), a traditional herbal formula, ameliorates murine lupus nephritis. • ZWT reduces renal tissue-resident CD8+ memory T (T RM) cells in vivo and in vitro. • It lowers the number of renal macrophages and decreases their expression of IL-15. • It also suppresses STAT3 phosphorylation in CD8+ T RM cells in vitro. [ABSTRACT FROM AUTHOR]

The dynamic adaptive immune responses elicited by the inactivated virus vaccine CoronaVac remain elusive. In a prospective cohort of 100 healthcare professionals naïve for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) who received two doses of CoronaVac, we analysed SARS-CoV-2-specific humoral and cellular responses at four different timepoints, including before vaccination (T1), 2 weeks after the first dose (T2), 2 weeks after the booster dose (T3), and 8–10 weeks after the booster dose (T4). SARS-CoV-2-specific antibodies, serum neutralizing activities, peripheral B cells, CD4+ and CD8+ T cells and their memory subsets were simultaneously measured in this cohort. SARS-CoV-2 spike-specific IgG responses reached a peak (geometric mean titre (GMT) 54827, 30969–97065) after two doses and rapidly declined (GMT 502, 212–1190) at T4, whereas suboptimal IgA responses were detected (GMT 5, 2–9). Spike-specific circulating B cells (0.60%, 0.46–0.73% of total B cells) and memory B cells (1.18%, 0.92–1.44% of total memory B cells) were effectively induced at T3 and sustained over time (0.33%, 0.23–0.43%; 0.87%, 0.05–1.67%, respectively). SARS-CoV-2-specific circulating CD4+ T cells (0.57%, 0.47–0.66%) and CD8+ T cells (1.29%, 1.04–1.54%) were detected at T3. At T4, 0.78% (0.43–1.20%) of memory CD4+ T cells and 0.68% (0.29–1.30%) of memory CD8+ T cells were identified as SARS-CoV-2-specific, while 0.62% (0.51–0.75%) of CD4+ T cells and 0.47% (0.38–0.58%) of CD8+ T cells were SARS-CoV-2-specific terminally differentiated effector memory cells. Furthermore, age and interval between doses affected the magnitude of CoronaVac-induced immune responses. SARS-CoV-2 memory CD4+ T cells were strongly associated with both receptor binding domain (RBD)-specific memory B cells (r 0.87, p <0.0001) and SARS-CoV-2-specific memory CD8+ T cells (r 0.48, p <0.0001). CoronaVac induced robust circulating and memory B cell and T cell responses. Our study offers new insight into the underlying immunobiology of inactivated virus vaccines in humans and may have implications for vaccine strategies in the future. [Display omitted] [ABSTRACT FROM AUTHOR]

• COVID-19 convalescents displayed an adaptive immune response for up to 7 months. • The T cell response is characterized by IFN-γ-, IL2-, and IFN-γ+IL2-secreting memory T cells. • Waning anti-SARS-CoV-2 IgG is associated with robust memory B cell and memory T cell responses. • The SNMO peptide pools elicited the strongest memory T cell response. Antiviral adaptive immunity involves memory B cells (MBC) and memory T cells (MTC). The dynamics of MBC and MTC in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) convalescents warrant further investigation. In this cross-sectional and longitudinal study, blood-derived MBC and MTC responses were evaluated in 68 anti-spike IgG-positive mild coronavirus disease 2019 (COVID-19) convalescents at visit 1, between 1 and 7 months (median 4.1 months) after disease onset. SARS-CoV-2 anti-spike IgG was determined by ELISA, MBC by SARS-CoV-2-specific receptor binding domain (RBD) ELISpot, and interferon gamma (IFN-γ)-, interleukin 2 (IL2)-, and IFN-γ+IL2-secreting MTC by IFN-γ and IL2 SARS-CoV-2 FluoroSpot. For 24 patients sampled at the first visit, the IgG, MBC, and MTC analyses were also performed 3 months later at the second visit. Seventy-two percent of convalescents were both MBC- and MTC-positive, 18% were MBC-positive and MTC-negative, and 10% were MTC-positive and MBC-negative. The peak MBC response level was detected at 3 months after COVID-19 onset and persisted up to 7 months post infection. Significant MTC levels were detected 1 month after onset in response to S1, S2_N, and SNMO peptide pools. The frequency and magnitude of the MTC response to SNMO was higher than those to S1 and S2_N. Longitudinal analysis demonstrated that even when specific humoral immunity declined, the cellular immunity persisted. The study findings demonstrate the durability of adaptive cellular immunity at least for 7 months after SARS-CoV-2 infection, suggesting long-lasting protection. [ABSTRACT FROM AUTHOR]

The development of manganese oxide-based chemodynamic immunotherapy is emerging as a key strategy against solid tumors. However, the limited efficacy of nanoplatform in inducing efficient tumor therapeutic effects and creating the prominent antitumor immune responses remains a crucial issue. In this study, we construct a novel multifunctional biomimetic nanovaccine comprising manganese oxide-loaded poly(2-diisopropylaminoethyl methacrylate) (MP) nanoparticles and a coating layer of hybrid cell membrane (RHM) derived from manganese oxide-remodeled 4T1 cells and dendritic cells (DCs) (collectively called MP@RHM) for combination chemodynamic immunotherapy. Compared with the nanovaccines coated with the single cell membrane, the MP@RHM nanovaccine highly efficiently activates both DCs and T cells to boost tumor-specific T cell, owing to the synergistic effects of abundant damage-associated molecular patterns, Mn2+, and T cell-stimulating moieties. Upon peritumoral injection, the MP@RHM nanovaccine targets both the tumor site for focused chemodynamic therapy and the lymph nodes for robust tumor-specific T cell priming, thereby achieving highly efficient chemodynamic immunotherapy. Moreover, as a preventive cancer nanovaccine, MP@RHM generates strong immunological memory to inhibit postoperative tumor metastasis and recurrence. Our study findings highlight a promising approach to construct a multifunctional biomimetic nanovaccine for personalized chemodynamic immunotherapy against solid tumors. [ABSTRACT FROM AUTHOR]

The presence of memory T cell specific for Trypanosoma cruzi in subjects with discordant serology for Chagas disease supports a cleared infection in these subjects. Using high-dimensional flow cytometry, ELISPOT assays and quantitative PCR, antibody-secreting cells and memory B cells specific for T. cruzi , total B-cell phenotypes, innate immune responses and parasite DNA were evaluated in serodiscordant, seropositive and seronegative subjects for T. cruzi infection. T. cruzi -specific memory B cells but no antibody-secreting cells specific for T. cruzi , increased proportion of nonclassical monocytes and increased levels of polyfunctional NK cells were found in serodiscordant compared with seropositive subjects. None of the serodiscordant subjects evaluated showed detectable parasite DNA, most of them did not show cardiac abnormalities and a group of them had had confirmed positive serology for Chagas disease. The unique immune profiles in serodiscordant subjects support that T. cruzi infection was cleared or profoundly controlled in these subjects. • Several serodiscordant subjects had been seropositive for T. cruzi infection. • Absence of parasite DNA in serodiscordant subjects. • T. cruzi -specific memory B cells in serodiscordant subjects. • Increased levels of nonclassical monocytes in serodiscordant subjects. • Highly functional NK cells in serodiscordant subjects. [ABSTRACT FROM AUTHOR]

Evolutionary adaptations in the Syngnathidae teleost family (seahorses, pipefish and seadragons) culminated in an array of spectacular morphologies, key immune gene losses, and the enigmatic male pregnancy. In seahorses, genome modifications associated with immunoglobulins, complement, and major histocompatibility complex (MHC II) pathway components raise questions concerning their immunological efficiency and the evolution of compensatory measures that may act in their place. In this investigation heat-killed bacteria (Vibrio aestuarianus and Tenacibaculum maritimum) were used in a two-phased experiment to assess the immune response dynamics of Hippocampus erectus. Gill transcriptomes from double and single-exposed individuals were analysed in order to determine the differentially expressed genes contributing to immune system responses towards immune priming. Double-exposed individuals exhibited a greater adaptive immune response when compared with single-exposed individuals, while single-exposed individuals, particularly with V. aestuarianus replicates, associated more with the innate branch of the immune system. T. maritimum double-exposed replicates exhibited the strongest immune reaction, likely due to their immunological naivety towards the bacterium, while there are also potential signs of innate trained immunity. MHC II upregulated expression was identified in selected V. aestuarianus -exposed seahorses, in the absence of other pathway constituents suggesting a possible alternative or non-classical MHC II immune function in seahorses. Gene Ontology (GO) enrichment analysis highlighted prominent angiogenesis activity following secondary exposure, which could be linked to an adaptive immune process in seahorses. This investigation highlights the prominent role of T-cell mediated adaptive immune responses in seahorses when exposed to sequential foreign bacteria exposures. If classical MHC II pathway function has been lost, innate trained immunity in syngnathids could be a potential compensatory mechanism. • Transcriptomic immune response assessments in seahorse (Hippocampus erectus). • Seahorses exposed in two phases to heat-killed Vibrio and Tenacibaculum strains. • Adaptive immune memory evidence (double-exposed) and increased naivety to Tenacibaculum. • Upregulated gene expression pertaining to potential innate 'trained immunity'. • Trained immunity potential compensator for deduced MHC II loss of function. [ABSTRACT FROM AUTHOR]

Although tumor-infiltrating T lymphocytes (TIL-Ts) play a crucial role in solid tumor immunotherapy, their clinical application has been limited because of the immunosuppressive microenvironment. Herein, we developed an injectable hydrogel microsphere-integrated training court (MS-ITC) to inspire the function of TIL-Ts and amplify TIL-Ts, through grafting with anti-CD3 and anti-CD28 antibodies and bovine serum albumin nanoparticles encapsulated with IL-7 and IL-15. MS-ITC provided the T-cell receptor and co-stimulatory signals required for TIL-Ts activation and IL-7/IL-15 signals for TIL-Ts expansion. Afterward, the MS-ITC was injected locally into the osteosarcoma tumor tissue in mice. MS-ITC suppressed the growth of primary osteosarcoma by more than 95 %, accompanied with primed and expanded TIL-Ts in the tumor tissues, compromising significantly increased CD8+ T and memory T cells, thereby enhancing the anti-tumor effect. Together, this work provides an injectable hydrogel microsphere-integrated training platform capable of inspiring TIL-Ts potential for a range of solid tumor immunotherapy. [ABSTRACT FROM AUTHOR]

An increasing number of evidences have shown that invertebrate taxa can be primed to produce immune memory to resist the secondary infection of pathogens, which was considered as a viable option to protect invertebrates from pathogens. In this work, we compared the protective effect of several different immune priming methods on the Vibrio alginolyticus secondary infection of the Crassostrea gigas. The results showed that C. gigas primed with live V. alginolyticus had higher ROS level, which led to hemocytes necrosis and higher mortality rate in the later stage. Low-dose of formalin-inactivated V. alginolyticus (including 5 × 104 CFU/mL and 5 × 105 CFU/mL) elicited appropriate immune response in C. gigas , protecting C. gigas from V. alginolyticus infection. Immersion with 5 × 104 CFU/mL formalin-inactivated V. alginolyticus was performed to prime C. gigas immunity in the trans -generational immune priming. Trans -generational immune priming significantly increased the resistance of larvae to various Vibrio species. Overall, these results suggested that low-dose of formalin-inactivated V. alginolyticus can protect C. gigas from secondary infection and confer broad-spectrum Vibrio resistance on offspring. This work provided valuable information toward a new direction for the protection of C. gigas from Vibrio infection. • Low-dose of formalin-inactivated Vibrio alginolyticus protected Crassostrea gigas from secondary infection. • Low-dose of formalin-inactivated V. alginolyticus elicited proper immune response in C. gigas during secondary infection. • The offspring of immune primed C. gigas was conferred board-spectrum Vibrio resistance. [ABSTRACT FROM AUTHOR]

Combination therapy based on sonodynamic therapy (SDT) combined with immune checkpoint blockers anti-PD-L1 provides effective anti-tumor effects. We designed a combination therapy based on M1/PLGA@IR780/CAT NPs of SDT-enhanced immunity combined with immune checkpoint blockers against PD-L1, which was based on M1 macrophage membrane-encapsulated poly (lactic-co-glycolic acid) (PLGA) nanoparticles loaded with the acoustic sensitizer IR780 and catalase (CAT) to successfully realize it. SDT based on M1/PLGA@IR780/CAT NPs could induce tumor cell death by promoting dendritic cell (DC) maturation and modulating the tumor immune microenvironment. In particular, the systemic anti-tumor immune response and potent immune memory induced upon combination with anti-PD-L1 checkpoint blockade not only alleviated the progression of mammary cancer in 4T1 mice and effectively blocked distant metastasis, but also prevented tumor recurrence, providing a promising new therapeutic strategy for clinical tumor therapy. [ABSTRACT FROM AUTHOR]

Hepatocellular carcinoma (HCC) has an insidious onset and high malignancy. Most patients have progressed to intermediate and advanced stages by the time of diagnosis, and the long-term efficacy of traditional treatments is not satisfactory. Immunotherapy has shown great promise in the treatment of HCC in recent years; however, the low immunogenicity and severe immunosuppressive tumor microenvironment result in a low response rate to immunotherapy in HCC patients. Therefore, it is of great significance to improve the immunogenicity of HCC and thus enhance its sensitivity to immunotherapy. Here, we prepared the boronophenylalanine-modified dual drug-loaded polydopamine nanoparticles by a facile method. This system used boronophenylalanine-modified polydopamine nanoparticles as a delivery vehicle and photothermal material for the chemotherapeutic drug doxorubicin and the immune agonist CpG oligodeoxynucleotides (CpG-ODN), with both active targeting and lysosomal escape functions. The cancer cells are rapidly killed by photothermal treatment, and then chemotherapy is used to further kill cancer cells that are inadequately treated by photothermal treatment. The combination of photothermal-chemotherapy synergistically induces the release of relevant antigens from tumor cells, thus initiating anti-tumor immunity; and then cooperates with CpG-ODN to trigger a powerful anti-tumor immune memory effect, potently and durably inhibiting HCC recurrence. [ABSTRACT FROM AUTHOR]

[Display omitted] • Cancer cell membrane proteins-based nanovaccines are easily prepared by MPNs. • Nanovaccines target DCs and elicit a robust antigen-specific cellular immunity. • Nanovaccines show admirable immunotherapy and prevention effects on tumors. Cancer nanovaccines offer a promising strategy for fighting against tumors, however, the engineering of cancer nanovaccines that can be easily fabricated with tanglesome cancer cell-derived antigens and elicit an adequately strong tumor-specific cellular immunity remains challenging. Herein, metal-phenolic networks (MPNs) are used as an antigen delivery platform to prepare the mannose-modified MPNs nanovaccine loaded with ovalbumin (OVA) and the immunoadjuvant CpG oligodeoxynucleotide (MMOC) through the facile self-assembly. When the model antigen OVA is substituted with cancer cell membrane proteins (CCMPs), the nanovaccine is called MMCC. MMOC markedly activates dendritic cells (DCs) via the mannose-mediated endocytosis and efficiently promotes the antigen cross-presentation, thus inspiring a robust antigen-specific CD8+ T cell response as well as immune memory effect in vivo. Consequently, MMOC exhibits admirable therapeutic and preventive results on E.G7-OVA tumors. Moreover, the combination use of MMCC with anti-PD1 significantly inhibits the growth of 4T1 tumors by strengthening the cellular immunity and decreasing the proportion of regulatory T cells (Tregs). The survival rate of 4T1 tumor-bearing mice in the prophylaxis assay is maintained at 100 % by MMCC over 42 days. Altogether, this study affords a universal and effective nanovaccine preparation strategy for cancer immunotherapy and prevention. [ABSTRACT FROM AUTHOR]

• A "Triple-Hop" nano-bomb UCNPs@SiO 2 -psoralen-K 2 FeO 4 @lauric acid-RGD (USPFLR), was prepared for tumor therapy. • Through the above "Triple-Hop" strategy, the USPFLR nano-bombs can attack tumor cells irreversibly at three levels. • USPFLR providing a referential application paradigm for tumor eradication and prevention of tumor recurrence. The development of non-interventional combination therapy with immune activation property provides a potential direction for solving the diversity, complexity and heterogeneity of malignant tumors. However, how to induce satisfactory immune activation by non-interventional treatment remains a great challenge. Herein, a "Triple-Hop" nano-bomb UCNPs@SiO 2 -psoralen-K 2 FeO 4 @lauric acid-RGD (USPFLR), was prepared and "detonated" after three steps. For step one, with NIR light as the "ignition" signal, USPFLR promoted the tumor to reach 40℃ and the phase transition of Lauric acid (LA) induced the release of K 2 FeO 4 and psoralen, triggering H 2 O 2 /GSH depletion and ·OH /O 2 production through multi-step cascade reactions of K 2 FeO 4 and psoralen-involved photodynamic therapy (PDT). For step two, high ROS release and direct DNA damage caused by psoralen further significantly triggered ferroptosis pathway and cGAS-STING pathway, which promoted the maturation of dendritic cells (DCs) and induced immune activation and immune memory in the third step. Therefore, through the first step of O 2 supply, GSH consumption and ROS generation, the second step of the activation of the ferroptosis pathway and cGAS-STING pathway and the third step of immune activation and immune memory, USPFLR nano-bombs successfully realized the "Triple-Hop" anti-tumor strategy, providing a referential application paradigm for tumor eradication and prevention of tumor recurrence. [ABSTRACT FROM AUTHOR]

• Targeting the BTLA-HVEM complex can modulate function of T cells. • Peptide inhibitors can interfere with BTLA-HVEM signaling. • Peptide drugs are promising immunomodulators in immune-related diseases. Immune checkpoints secure the proper function of the immune system and the maintenance of the BTLA-HVEM complex, an inhibitory immune checkpoint, is one of the pathways vital for T cell responsiveness to various stimuli. The present study reports the immunomodulatory potential of five peptides targeting the BTLA-HVEM complex on the activity of human T cells. Isolated T cells were exposed to the peptides alone or combined with CD3/CD28 mAb for 72 h or 120 h. The flow cytometry was used to evaluate the activation markers (CD69, CD62L, CD25), changes within the T cell memory compartment, proliferation rate, and apoptosis of T cells. The immunomodulatory effect of the peptides was visible as an increase in the percentage of CD4+ and CD8+ T cells expressing CD69 or CD25, a boost in T cell proliferation, and shifts in the T cell memory compartment. Pep(2) and Pep(5) were the most promising compounds, displaying a putative immune-restoring function. [Display omitted] [ABSTRACT FROM AUTHOR]

In this issue of Cancer Cell , Anadon et al. perform a multi-omics analysis of ovarian tumor infiltrating tissue-resident memory T (TRM) cells at the single-cell level that supports a differentiation model from CD103−TCF1+ re-circulating T-cell precursors driven by tumor antigen recognition. CD103+ TRM cells play a dominant anti-tumor role in ovarian cancer. [ABSTRACT FROM AUTHOR]

• Vaccine elicited immune response in majority of the individuals. • Previously infected individuals showed higher neutralizing antibody response. • Higher memory cell response seen in previously infected individuals. • Single dose vaccination in previously exposed individuals is an efficient strategy. • Such a strategy enables larger population coverage. The efficacy of COVID-19 vaccines to generate immunological memory post-vaccination has not previously been studied. To assess immunological memory in previously SARS-CoV-2 infected individuals after a single dose of mRNA vaccine. Healthcare workers (n = 280) were enrolled after obtaining written informed consent and grouped under previously infected and no prior exposure (reverse transcription-polymerase chain reaction positive and negative, respectively). Blood was drawn at baseline and post-vaccination (single dose of COVISHIELD) for enumerating neutralizing antibodies by chemiluminescence and memory T- and B-cells by flow cytometry. Post vaccination, compared with the no prior exposure group, the previously infected group had higher levels of: antibody response (1124.73 ± 869.13 vs 94.23 ± 140.06 AU/ml, p = 0.0001); CD4 memory T-cells: central memory CCR7+CD45RA- (p = 0.0001), effector memory CCR7-/CD45RA- (p = 0.01); total CD8+ T-cells (p = 0.004); CD8+ naïve T-cells CCR7+CD45RA+ (p = 0.01); and memory B-cells CD20+CD27+ (p = 0.0001). Single-dose vaccination elicited higher neutralizing antibody response and protective immunity in individuals who had recovered from SARS-CoV-2 infection compared with those with no prior exposure. [ABSTRACT FROM AUTHOR]

[Display omitted] • Phages are T-dependent antigens; phage-specific immune response is common and similar to that induced by many other antigens. • Controlling effective doses may help in controlling the immune response to phage. • Phage therapy design may benefit from predicting possible cross-reactions between antibodies specific to different phages. • Identification of phage-specific epitopes could be an important part of phage characterization. Antibodies specific to phage virions have been observed many times, both in animals and in humans. Phages induce the T-dependent type of immune response, which is fundamental for immunological memory and long retention of abilities to recognize and respond to foreign epitopes. Experimental models have shown that phage-specific antibodies can be devastating for a phage in vivo. Observations from phage treatment in humans demonstrate however that antibodies do not necessarily hinder phage therapy. Controlling effective doses may help in controlling the immune response to phage and to create 'therapeutic windows' for the phage. Phage therapy design may also benefit from understanding phage antigenicity and predicting possible cross-reactions between antibodies specific to different phages. [ABSTRACT FROM AUTHOR]

• Construction of a stable ternary biomedicine without extra drug excipient. • Upregulating NLRP3 to promote PDT induced cell pyroptosis. • Immune activation by pyroptosis induction and IDO inhibition for tumor inhibition. The development of immunotherapy is seriously limited by the insufficient tumor immunogenicity and immunosuppressive microenvironment. Pyroptosis is a new form of immunogenic cell death (ICD) associated with the gasdermin protein family, which has received increasing attention as a promising approach to activate antitumor immunity. Herein, we construct a ternary biomedicine (CNS) based on the self-assembly of photosensitizer chlorine e6 (Ce6), NLG919 (NLG) and simvastatin (Sim), which has a fairly high drug content, good stability and uniform morphology. Interestingly, the photodynamic therapy of CNS can generate reactive oxygen species (ROS) to induce intracellular oxidative stress, activating NOD-like receptor thermal protein domain associated protein 3 (NLRP3)/Caspase-1 (Cas-1)/gasdermin D N-terminal domain (GSDMD-N) dependent pyroptosis. Further, Sim-mediated NLRP3 upregulation will also promote cell pyroptosis to activate ICD and stimulate immune responses. Benefiting from NLG-induced indoleamine 2,3-dioxygenase (IDO) inhibition, CNS is capable of improving the immunosuppressive microenvironment to enhance immunotherapy. Consequently, the pyroptosis induction synergized with IDO inhibition of CNS exhibits excellent antitumor immune activities, as evidenced by enhancing DCs maturation and effector memory T cells frequency, which significantly inhibit tumor growth and metastasis. This proposal of self-delivery ternary nanomedicine might open a new window to construct drug delivery systems for pyroptosis activated immunotherapy. [ABSTRACT FROM AUTHOR]

Dual therapy (DT) has shown comparable results to triple therapy (TT) in efficacy and other immunological aspects. However, there are still some concerns about DT, including several immunological features. Therefore, we evaluated whether HIV-1-specific memory T-cell responses and exhaustion phenotypes are adversely influenced after simplification to DT. HIV-1-specific CD4+ and CD8+ T-cell responses were assessed by intracellular cytokine and degranulation marker staining, and polyfunctionality indexes after stimulation with a Gag peptide pool. Exhaustion phenotypes were evaluated by PD-1, TIM-3, and LAG-3 expression in CD4+ and CD8+ T cells. Forty participants in the TRIDUAL trial (ClinicalTrials.gov: NCT03447873) who were randomized to continue integrase inhibitor-based TT (n = 20) or to switch to DT (dolutegravir or darunavir/cobicistat plus lamivudine) (n = 20). After 96 weeks, the magnitude of CD4+ and CD8+ T-cell responses was similar in both treatment arms (p = 0.221 and p = 0.602, respectively). The CD4+ polyfunctionality index decreased in the TT arm (p = 0.013) and remained stable in the DT arm, while the polyfunctionality of CD8+ T cells was unchanged in both arms. There was a significant decrease in the expression of PD-1, TIM-3, and the co-expression of PD-1+TIM-3+LAG-3+, and PD-1 +TIM-3 + in both CD4+ and CD8+ T cells. However, the decrease in the expression of exhaustion markers did not improve HIV-1-specific T-cell responses. Our results suggest that simplification to DT does not negatively influence the HIV-1-specific T-cell response or the exhaustion phenotype after 96 weeks of follow-up. [Display omitted] • Dual therapy (DT) has similar results in efficacy and immunological aspects than triple therapy. • The impact of DT on HIV-1-specific immunity needs to be clarified. • Twenty participants continued with triple therapy and 20 switched to DT. • HIV-1-specific T-cell responses are not negatively affected by simplification to DT. • T-cell exhaustion displayed a comparable drop after 96 weeks in both treatment arms. [ABSTRACT FROM AUTHOR]

• The first targeted platform of framework nucleic acid for radiotherapy is presented. • This delivery platform is ATP-targeted and can assist in low-dose radiotherapy. • The anti-tumor immune response is enhanced by promoting the maturation of DCs. Traditional radiotherapy is ineffective against some aggressive and recurrent tumors. In clinical therapy, low-dose radiations are frequently utilized to lessen the negative effects of X-rays. There is an urgent need to develop a novel therapeutic strategy for adjuvant radiotherapy. An ATP-responsive and functionalized framework nucleic acid delivery system (Op-TGA) was developed using local irradiation, which can cause enormous ATP release from tumors. The framework nucleic acid carrying the nucleic acid fragment of immune adjuvant and antigen peptides can be massively aggregated and successfully released in a high-concentration ATP environment using this delivery platform. Thus, intravenous injection of Op-TGA into tumor-bearing mice after radiation can precisely concentrate around the tumor tissue, and once released, it is rapidly taken up by antigen-presenting cells, stimulating the cellular immune response. The conjunction of radiotherapy and Op-TGA has a significant synergistic anticancer efficacy and establishes an immunological memory effect to prevent tumor recurrence. Op-TGA developed here offers a new technique for Radio-immunotherapy that is closely related to clinical therapy and has great clinical application potential. [ABSTRACT FROM AUTHOR]

Vaccines remain one of the most important pillars in preventative medicine, providing protection against a wide array of diseases by inducing humoral and/or cellular immunity. Of the many possible candidate antigens for subunit vaccine development, carbohydrates are particularly appealing because of their ubiquitous presence on the surface of all living cells, viruses, and parasites as well as their known interactions with both innate and adaptive immune cells. Indeed, several licensed vaccines leverage bacterial cell-surface carbohydrates as antigens for inducing antigen-specific plasma cells secreting protective antibodies and the development of memory T and B cells. Carbohydrates have also garnered attention in other aspects of vaccine development, for example, as adjuvants that enhance the immune response by either activating innate immune responses or targeting specific immune cells. Additionally, carbohydrates can function as immunomodulators that dampen undesired humoral immune responses to entire protein antigens or specific, conserved regions on antigenic proteins. In this review, we highlight how the interplay between carbohydrates and the adaptive and innate arms of the immune response is guiding the development of glycans as vaccine components that act as antigens, adjuvants, and immunomodulators. We also discuss how advances in the field of synthetic glycobiology are enabling the design, engineering, and production of this new generation of carbohydrate-containing vaccine formulations with the potential to prevent infectious diseases, malignancies, and complex immune disorders. • Glycans play a role in nearly every aspect of innate and adaptive immunology. • Many licensed vaccines leverage bacterial cell-surface carbohydrates as antigens. • Many glycans are used as adjuvants that enhance immune responses. • Glycans are used as delivery systems that promote specific immune cell or tissues. • Glycans are used as dampeners that suppress undesired humoral immune responses. [ABSTRACT FROM AUTHOR]

Exposure to mercury (Hg) and silver (Ag) has been shown to induce autoimmune diseases in genetically susceptible rodents. Here, A.SW mice were initially exposed to HgCl 2 , AgNO 3 or tap water (control) for 3 weeks. After 13 weeks of stoppage, all mice had secondary exposure to 203HgCl 2. After secondary exposure, higher and earlier ANoA titers were observed in mice initially exposed to Hg or Ag compared to control. Further, mice initially exposed to Ag showed higher total IgG 1 and IgG 2a , Whole Body Retention and lymph nodes and spleen accumulation of Hg compared to mice initially exposed to Hg and controls. These findings showed an earlier and stronger immunological response in A.SW mice compared with control, following re-exposure to heavy metals indicating an immunological memory. Additionally, secondary exposure to a different heavy metal may aggravate the effects of exposure of at least one of the metals indicating cross-reactivity. • We evaluated if a primary exposure to Hg or Ag in A.SW mice induces immunological memory. • A.SW mice were primary exposed to Hg or Ag and secondary to 203Hg. • Secondary exposure triggered an earlier and stronger immunological response. • Different heavy metals may aggravate the effects of exposure to one. [ABSTRACT FROM AUTHOR]

Radiosensitization efficacy of conventional tumor radiosensitizers has been frequently limited by insufficient competence for tumor microenvironment (TME) regulation and unfavorable cellular uptake at biological barriers. Here, we reported an ultra-efficient radiotherapy (RT) strategy by synthesizing an extracellular vesicles (EVs)-encapsulated hollow MnO 2 to load metformin (Met@HMnER). It demonstrated significant RT enhancement by morphological control of catalyst and cellular respiratory depression against conventional solid MnO 2. Furthermore, the target-modified EVs clothing retains outstanding metformin loading capacity while endowing enhanced biological barrier penetration. A noticeably durable innate immune activation of NK cells was triggered with this nanoplatform via the cGAS-STING pathway. The enhanced immunocompetence was verified on distal metastasis and in-situ recurrence model in vivo , This work paved a new path for synergistic and robust innate immunity in clinical cancer treatment. [Display omitted] [ABSTRACT FROM AUTHOR]

The success of mRNA-based vaccines during the Covid-19 pandemic has highlighted the value of this new platform for vaccine development against infectious disease. However, the CD8+ T cell response remains modest with mRNA vaccines, and these do not induce mucosal immunity, which would be needed to prevent viral spread in the healthy population. To address this drawback, we developed a dendritic cell targeting mucosal vaccination vector, the homopentameric STxB. Here, we describe the highly efficient chemical synthesis of the protein, and its in vitro folding. This straightforward preparation led to a synthetic delivery tool whose biophysical and intracellular trafficking characteristics were largely indistinguishable from recombinant STxB. The chemical approach allowed for the generation of new variants with bioorthogonal handles. Selected variants were chemically coupled to several types of antigens derived from the mucosal viruses SARS-CoV-2 and type 16 human papillomavirus. Upon intranasal administration in mice, mucosal immunity, including resident memory CD8+ T cells and IgA antibodies was induced against these antigens. Our study thereby identifies a novel synthetic antigen delivery tool for mucosal vaccination with an unmatched potential to respond to an urgent medical need. [Display omitted] [ABSTRACT FROM AUTHOR]

Recent studies have suggested that innate immune responses exhibit characteristics associated with memory linked to modulations in both vertebrates and invertebrates. However, the diverse evolutionary paths taken, particularly within the invertebrate taxa, should lead to similarly diverse innate immunity memory processes. Our understanding of innate immune memory in invertebrates primarily comes from studies of the fruit fly Drosophila melanogaster, the generality of which is unclear. Caenorhabditis elegans typically inhabits soil harboring a variety of fatal microbial pathogens; for this invertebrate, the innate immune system and aversive behavior are the major defensive strategies against microbial infection. However, their characteristics of immunological memory remains infantile. Here we discovered an immunological memory that promoted avoidance and suppressed innate immunity during reinfection with bacteria, which we revealed to be specific to the previously exposed pathogens. During this trade-off switch of avoidance and innate immunity, the chemosensory neurons AWB and ADF modulated production of serotonin and dopamine, which in turn decreased expression of the innate immunity-associated genes and led to enhanced avoidance via the downstream insulin-like pathway. Therefore, our current study profiles the immune memories during C. elegans reinfected by pathogenic bacteria and further reveals that the chemosensory neurons, the neurotransmitter(s), and their associated molecular signaling pathways are responsible for a trade-off switch between the two immunological memories. [ABSTRACT FROM AUTHOR]

• Pseudomonas aeruginosa antibody response impaired after lung transplantation. • Antibody count after lung transplantation is independent of infectious status. • A long-term and individual immunological response persists in cystic fibrosis. • The first P. aeruginosa antibody response elicits the longest lasting one. Specific Pseudomonas aeruginosa (PA) precipitating immunoglobulin G antibodies in serum are correlated with PA biofilm infection and are used as diagnostic and prognostic markers in cystic fibrosis (CF). The aim of this study was to examine the change of PA antibody response in CF patients after bilateral sequential lung transplantation (LTx). PA antibodies and airway bacteriology were retrospectively evaluated in 20 chronically infected CF patients, who underwent LTx between 2001 and 2016 at Rigshospitalet, Copenhagen. Yearly precipitin counts from one year before LTx and up to five years after LTx were compared. Monthly airway cultures were examined in the five-year period after LTx. In addition, crossed immunoelectrophoresis (CIE) were analysed for each patient for antigenic similarities from time of infection, pre-LTx and post-LTx. All patients experienced a significant drop in PA antibodies from one year pre-LTx to one year post-LTx (p < 0.0001). The PA antibody level did not differ between those, who became reinfected immediately after LTx, and those, who did not. No patients regained the high pre-LTx precipitin levels in the following five years. The antigenic specificities of the sera post-LTx were in each patient similar to the antigenic specificities at the beginning of infection indicating a decades long memory of their immune response like an "immunological fingerprint". After LTx a significant and continuous reduction in PA antibodies was observed. The reduction was independent of immediate reinfection after LTx. A novel three-factor explanatory model is presented. [ABSTRACT FROM AUTHOR]

Immune cells are capable of sensing various signals in the microenvironment and turning on specific immune functions in response. The appropriate transition of immune cells into diverse functional states, which is crucial for immunity, involves complex and well-regulated changes in transcriptional program. Accumulating evidence shows that epigenetic remodeling plays a central role in mediating the transcriptional program for immune cell activation and immunological memory. Concurrently, immune cells undergo significant metabolic reprogramming during immune response. Here we review recent studies that demonstrate shifts in metabolic state can orchestrate immune cell functions through its impact on epigenetic remodeling, and the microenvironment can exert its influence on immune cells through the metabolic regulation of epigenetics. We also discuss the systems biology approaches that enabled these discoveries. [ABSTRACT FROM AUTHOR]

Despite the importance of immunological memory for protective immunity against viral infection, whether H7N9-specific antibodies and memory T-cell responses remain detectable years after the original infection is unknown. A cross-sectional study was conducted to investigate the immune memory responses of H7N9 patients who contracted the disease and survived during the 2013–2016 epidemics in China. Sustainability of antibodies and T-cell memory to H7N9 virus were examined. Healthy individuals receiving routine medical examinations in a physical examination centre were recruited as control. A total of 75 survivors were enrolled and classified into four groups based on the time elapsed from illness onset to specimen collection: 3 months (n = 14), 14 months (n = 14), 26 months (n = 28) and 36 months (n = 19). Approximately 36 months after infection, the geometric mean titres of virus-specific antibodies were significantly lower than titres in patients 3 months after infection, but 16 of 19 (84.2%) survivors in the 36-month interval had microneutralization (MN) titres ≥40. Despite the overall declining trend, the percentages of virus-specific cytokine-secreting memory CD4+ and CD8+ T cells remained higher in survivors at nearly all time-points in comparison with control individuals. Linear regression analysis showed that severe disease (mean titre ratio 2.77, 95% CI 1.17–6.49) was associated with higher haemagglutination inhibition (HI) titre and female sex for both HI (1.92, 1.02–3.57) and MN (3.33, 1.26–9.09) antibody, whereas female sex (mean percentage ratio 1.69, 95% CI 1.08–2.63), underlying medical conditions (1.94, 95% CI 1.09–3.46) and lack of antiviral therapy (2.08, 95% CI 1.04–4.17) were predictors for higher T-cell responses. Survivors of H7N9 virus infection produced long-term antibodies and memory T-cell responses. Our findings warrant further serological investigation in general and high-risk populations and have important implications for vaccine design and development. [ABSTRACT FROM AUTHOR]

Some strains of Bacillus Calmette–Guérin (BCG) vaccine not only confer protection against disseminated forms of tuberculosis, but also reduce all-cause mortality by the induction of protection against infections with non-related pathogens. We review evidence for non-specific protection induced by BCG vaccination against viral infections, discuss possible mechanisms of action, and summarize implications for vaccination policies and vaccine discovery. Relevant studies retrieved from PubMed and clinicaltrials.gov. Numerous epidemiological, clinical and immunological studies demonstrate that BCG vaccination impacts the immune response to subsequent infections, resulting in reduced morbidity and mortality. Important lines of evidence indicating that BCG protects against viral pathogens comes from experimental studies in mice showing that BCG offers protection against various DNA and RNA viruses, including herpes and influenza viruses. Recently, the effect of BCG on an experimental viral infection in humans has been demonstrated. These effects are thought to be mediated via the induction of innate immune memory and heterologous lymphocyte activation, resulting in enhanced cytokine production, macrophage activity, T-cell responses and antibody titres. The discovery of innate immune memory has greatly improved our understanding of the mechanisms underlying the non-specific effects induced by BCG vaccination. However, a full understanding of the molecular mechanisms that underlie this phenomenon is still evolving. By identifying the factors that impact the non-specific effects of BCG, we will take an important step towards novel therapeutic options and vaccination strategies, which might lead to a reduction in severe morbidity and mortality associated with viral infections. [ABSTRACT FROM AUTHOR]

Vaccines induce antigen-specific memory in adaptive immune cells that enables long-lived protection against the target pathogen. In addition to this, several vaccines have beneficial effects greater than protection against their target pathogen. These non-specific effects are proposed to be the result of vaccine-induced immunomodulation. In the case of bacille Calmette–Guérin (BCG) vaccine, this involves induction of innate immune memory, termed 'trained immunity', in monocytes and natural killer cells. This review discusses current evidence for vaccine-induced immunomodulation of adaptive immune cells and heterologous adaptive immune responses. The three vaccines that have been associated with changes in all-cause infant mortality: BCG, diphtheria–tetanus–pertussis (DTP) and measles-containing vaccines (MCV) alter T-cell and B-cell immunity. The majority of studies that investigated non-specific effects of these vaccines on the adaptive immune system report changes in numbers or proportions of adaptive immune cell populations. However, there is also evidence for effects of these vaccines on adaptive immune cell function and responses to heterologous stimuli. There is some evidence that, in addition to BCG, DTP and MCV, other vaccines (that have not been associated with changes in all-cause mortality) may alter adaptive immune responses to unrelated stimuli. This review concludes that vaccines alter adaptive immune cell populations and heterologous immune responses. The non-specific effects differ between various vaccines and their effects on heterologous adaptive immune responses may also involve bystander activation, cross-reactivity and other as yet undefined mechanisms. This has major implications for future vaccine design and vaccination scheduling. [ABSTRACT FROM AUTHOR]

We aimed to investigate immunity against hepatitis B surface antigen (HBsAg) mutants before and after boosters in adolescents who had lost antibodies against HBsAg (anti-HBs) despite neonatal vaccination. We recruited 142 participants from 15 to 21 years old who had received complete vaccination in infancy but became anti-HBs-negative. Cellular immunity to HBsAg and T-cell epitope variants was assessed before and after boosters. Antibody affinity to variants was assessed after boosters. After one dose of booster, 12 out of 140 (8.6%) participants remained anti-HBs-negative. Anti-HBs titres were higher in those participants <17 (geometric mean, 337.9 ± 10.9 vs. 157.4 ± 16.6 mIU/mL, p = 0.012). Before the booster, HBsAg-specific cell proliferation was present in 58 out of 64 (90.6%) participants. The proliferation response rates to T-cell epitopes were 37.8% and 72.6% (p < 0.001) before and after the booster, respectively. The stimulation index improved from 1.25 ± 1.70 to 2.53 ± 2.32 (p < 0.001) for various T-cell epitopes. HBsAg-specific interleukin (IL)-5- and interferon (IFN)-γ-secreting T-cells were enhanced (45 ± 10 and 50 ± 4 to 420 ± 328 and 355 ± 424 spot-forming cells/106 cells, respectively, p < 0.001). IFN-γ-secreting T cells to epitope 16-33 containing R24K and the antibody affinity to sG145R were still significantly lower than to the wild type. In immunized adolescents who lost anti-HBs, around 10% also lost immune memory. Cellular immunity to some T-cell epitope variants improved after the booster. Antibody affinity to sG145R and the IFN-γ-secreting cell response to some epitope 16-33 variants were still impaired even after booster administration. [ABSTRACT FROM AUTHOR]

• Probiotic-derived selenium (Se) nanoparticles acted as the immune adjuvant. • HBO effectively promoted the Se-mediated O 2 – generation to boost tumor CDT. • HBO largely ameliorated the immunosuppressive tumor microenvironment. Chemodynamic therapy (CDT) was a promising approach to enhance the immunogenicity of tumor cells for potentiating immune checkpoint blockade (ICB) therapy, but usually suffered from hypoxia and immunosuppressive tumor microenvironment. Herein, we developed a hyperbaric oxygen (HBO)-strengthened CDT-nanoadjuvants platform (Se@OMV-GOx-HA) by modifying probiotic-derived selenium (Se) nanoparticles with glucose oxidase (GOx) and hyaluronic acid (HA) to boost αPD-L1-medaited ICB therapy against breast cancer. In the presence of H 2 O 2 and glutathione (GSH), Se@OMV acted as nanoenzyme to mediate the electron transfer from GSH to O 2 giving O 2 –, while GOx catalyzed the production of H 2 O 2. Synergistically, HBO effectively improved tumor hypoxia to foster GOx-catalyzed oxidation of glucose to H 2 O 2 , then provided the essential fuels including H 2 O 2 and O 2 for Se-mediated O 2 – generation, causing strong immunogenic cell death (ICD) effect to enhance the immunogenicity of tumor cells. Under co-stimulation by Se@OMV acting as immunoadjuvants, maturation of dendritic cells and priming of cytotoxic T cells were largely promoted. Assisted by HBO, infiltration of cytotoxic T cells in mice tumor was significantly improved, which not only generated long-term antitumor immune memory, but largely boosted αPD-L1-medaited ICB therapy. Given the clinical available of HBO, this nanosystem has great clinical translation potential for cancer CDT/immunotherapy. [ABSTRACT FROM AUTHOR]

• Combination of DTQE-3+ with Poly(I:C) for photodynamic-immuno bimodal therapy. • P@AP composite nanoparticles induce ICD and promote antigen presentation massively. • Recruitment of pAPC by nanoparticle facilitates antigen cross-presentation in vivo. • Bimodal therapy with photodynamic and immune boosts the prognosis of melanoma. Nanoparticles offer a promising platform for drug delivery due to their long circulation time, enhanced solubility, low toxicity and excellent targeting of lesions. Herein, we report an AIEgen -Poly (I:C) composite nanoparticle (P@AP) for dual-modality tumor photodynamic-immunotherapy. Its specific size and capacity for partial degradation under acidic conditions determine its enhanced EPR effect. By complexing with the immunoadjuvant Poly(I:C), the immune silencing mechanism induced by apoptosis can be overcome and ICD is evoked efficiently at the cellular level. In the process of antigen presentation, P@AP , as an exogenous antigen, on the one hand, strengthens the expression of antigen presentation signal molecule MHC II and activates CD4+ T cells, on the other hand, enhancing pAPC infiltration by the increase of endogenous antigens represented by damage-associated molecular patterns while expressing MHC I via antigenic cross-presentation remarkably induces activation of CD8+ T cells, directly enhancing the killing of target cells. Massive immune arousal results in sustained tissue-resident memory T-cell residency in melanoma and reduces expression of CD4+ subsets of Treg cells, thereby prolonging the survival of subcutaneous melanoma mice and ridding of the poor prognosis of malignant melanoma stemming from its auto-immunosuppressive properties. [ABSTRACT FROM AUTHOR]

Cernunnos deficiency is a rare genetic disorder characterized by immunodeficiency, microcephaly, growth retardation, bird-like facies, sensitivity to ionizing radiation, few autoimmune manifestations, premature aging of hematopoietic stem cells at an early age, and occasional myeloproliferative disease. Herein we present five Egyptian Cernunnos patients from 3 different families. We describe the patients' clinical phenotypes, their immunological profile as well as genetic results. Sequence analysis revealed three different mutations in the NHEJ1 gene: a nonsense variant c.532C > T; p.(Arg178Ter), an intronic variant c.178-1G > A and a frameshift insertion variant c.233dup; p.(Asn78LysfsTer14). In conclusion, Cernunnos deficiency can have a wide range of clinical features. The characteristic immune profile including a decrease in recent thymic emigrants and naive T cells, markedly elevated memory T cells together with normal to high IgM, and a decrease in IgG and IgA. This immune profile is highly suggestive of Cernunnos deficiency in T-B-NK + SCID patients especially surviving for older ages. • This is the first Egyptian report of patients with mutations in NHEJ1 gene. • c.532C > T; p.(Arg178Ter), c.178-1G > A and c.233dup had been identified in NHEJ1 gene. • Cernunnos deficiency can have a wide range of clinical features. • Suspicion is raised in SCID with elevated memory and decrease naïve T cells. • Presence of BM aplasia and absence of malignancies are disease hallmarks. [ABSTRACT FROM AUTHOR]

The efficacy of photodynamic therapy (PDT) is severely limited by the hypoxic tumor microenvironment (TME), while the performance of PDT-aroused antitumor immunity is frustrated by the immunosuppressive TME and deficient immunogenic cell death (ICD) induction. To simultaneously tackle these pivotal problems, we herein create an albumin-based nanoplatform co-delivering IR780, NLG919 dimer and a hypoxia-activated prodrug tirapazamine (TPZ) as the dual enhancer for synergistic cancer therapy. Under NIR irradiation, IR780 generates 1O 2 for PDT, which simultaneously cleaves the ROS-sensitive linker for triggered TPZ release, and activates its chemotherapy via exacerbated tumor hypoxia. Meanwhile, firstly found by us, TPZ-mediated chemotherapy boosts PDT-induced tumor ICD to evoke stronger antitumor immunity including the development of tumor-specific cytotoxic T lymphocytes (CTLs). Eventually, enriched intratumoral GSH triggers the activation of NLG919 to mitigate the immunosuppressive TME via specific indoleamine 2,3-dioxygenase 1 (IDO-1) inhibition, consequently promoting the intratumoral infiltration of CTLs and the killing of both primary and distant tumors, while the resultant memory T cells allows nearly 100% suppression of tumor recurrence and metastasis. This nanoplatform sets up an example for dully enhanced photodynamic immunotherapy of breast cancer via hypoxia-activated chemotherapy, and paves a solid way for the treatment of other hypoxic and immunosuppressive malignant tumors. [Display omitted] [ABSTRACT FROM AUTHOR]

• Sustained use of clean fuel for cooking reduced household air pollution (HAP). • Exclusive LPG use for 26 months reduced personal PM 2.5 and CO exposure. • Sustained reductions in HAP decreased CD8+T, T regulatory and CD19+B cells. • Reduced HAP exposure increased CD4+T cells, plasmablasts, early & memory B cells. We conducted a clean fuel intervention trial (Bangladesh Global Environmental and Occupational Health (GEOHealth) (NCT02824237) with liquefied petroleum gas (LPG) for 26 months among rural Bangladeshi women chronically exposed to household air pollution (HAP) from biomass fuel (BMF) use. We aimed to evaluate the effect of HAP reduction following LPG intervention on immune response outcome. We supplied LPG cook stove and refills in cylinder in 200 households for 26 months. We measured personal exposure to HAP [particulate matter 2.5 (PM 2·5), black carbon (BC) and carbon monoxide (CO)] in 200 women (main cook) by personal monitors at pre- and post-intervention. Immune function was assessed before and after intervention, in blood collected within 2 weeks of HAP measurements. Primary endpoints included reduction in HAP, lymphocyte proliferation and oxidative stress response, and alterations in T and B cell proportions. Exclusive LPG use for 26 months resulted in significant reduction in PM 2·5 (43.5%), BC (13%) and CO (48%) exposure in the women. For one unit decrease in BC, Treg cells and memory B cells increased by 7% and 34% respectively, in the peripheral circulation. One unit decrease in CO was significantly associated with increase in early B cells and plasmablasts by 66% and 5% respectively. For one unit decrease in BC, percent-dividing cells, proliferation and expansion indices increased by 2%, 0.4%, and 1%, respectively. Reduced personal exposure to HAP through clean fuel intervention was related to a return towards cellular immune balance. [ABSTRACT FROM AUTHOR]