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Photothermal therapy (PTT) is a cancer-targeted treatment approach.The occurrence of tumors may be related to microbial infections (Viruses, bacteria, fungi, etc.), which probably provokes anti-tumor immunity. However, T cells in the context of cancer become exhausted and dysfunctional. Galectin-9 (Gal-9) is highly expressed in normal tissues and associates with body immune tolerance, and was firstly evidenced with much higher expression on the primary solid tumors than CD80/86 (B7) and CD274 (PD-L1) here, which suggests that Gal-9 may be a key factor in inhibiting the anti-tumor immunity, and its receptor T cell immunoglobulin and mucin domain 3 (TIM-3) was discovered on the cytotoxic T lymphocytes (CTL) with high expression as well based on the single cell analysis. The immune checkpoint communications showed that the Gal-9/TIM-3 axis played the most vital role on negatively regulating the anti-tumor immunity of CTL for melanoma. Then, we used a novel transdermal photothermal nanosensitizer (FSGG) loading Gal-9 siRNA (FSGG/siGal-9) for knocking the tumor cells down Gal-9 to block the Gal-9/TIM-3 axis and prohibit CTL exhaustion synergizing PTT against melanoma, which evidenced good effects on inhibiting tumor growth and enhancing anti-tumor immunity, named "photothermal immunotherapy". This paper provides a new perspective for tumor prevention and treatment. This study explores the synergistic effects of photothermal therapy and silencing Gal-9 to achieve photothermal immunotherapy treating melanoma with an integrated FSGG nanostructure. [ABSTRACT FROM AUTHOR]

This paper addresses the controversy of Granzyme B (GzmB) expression by murine Myeloid Derived Suppressor Cells (MDSCs). MDSCs are a heterogenous immature myeloid population that are generated in chronic inflammatory pathologies for the purpose to suppress inflammatory responses. MDSCs express a multitude of factors to induce suppressive function such as PD-L1, reactive oxygen species (ROS), nitric oxide synthase (iNOS), and Arginase-1. Recently, Dufait et al. sought to demonstrate GzmB as an additional mechanism for suppression by MDSCs. They reported that murine MDSCs not only significantly express GzmB as well as Perforin (Prf1), but this expression is functionally important for tumor growth in vivo as well as tumor migration in vitro. We conducted experiments to address the same question but made confounding observations: MDSCs under stringent developmental process do not express GzmB. Our results show that not only GzmB protein is not produced at functional level, but the mRNA transcript is not detectable either. In fact, the GzmB protein found in the media of MDSC culture was due to T cells or natural killer cells contained in bone marrow and cultured alongside MDSCs. We strengthen this finding by genetically deleting GzmB from the myeloid lineage and measuring tumor burden compared to WT counterpart. Our results show no significant difference in tumor burden, suggesting that even if there is minor expression of GzmB, it is not produced at a functional amount to affect tumor growth. Therefore, this paper proposes alternative theories that align with the known understanding of GzmB expression and secretion. [ABSTRACT FROM AUTHOR]

Objective and design: This systematic review aims to establish the role of CD8 + T lymphocytes in COPD. Methods: Forty-eight papers published in the last 15 years were identified for inclusion. Results: CD8 + T-cells are increased in the lungs of patients with COPD (17 studies, 16 positive) whereas in the circulation, findings were inconclusive. Activation of CD8 + T-cells was enhanced in lungs (four studies, three positive) but cell phenotype was unclear. There was substantial evidence of a higher proportion of type 1 CD8 + (Tc1) cells in COPD (11 studies, 9 positive), though the population of type 2 (Tc2) cells was also increased (5 studies, 4 positive). CD8 + T-cells in COPD exhibited greater expression of cytotoxic proteins (five studies, five positive). Studies assessed a variety of questions so evidence was insufficient to draw firm conclusions. The role of CD8 + T-cells at acute exacerbation of COPD and also their contribution to alveolar destruction can only be hypothesised at this stage. Conclusions: Not only is the number of CD8 + T-cells increased in COPD, these cells have increased capacity to exert effector functions and are likely to contribute to disease pathogenesis. Several mechanisms highlighted show promise for future investigation to consolidate current knowledge. [ABSTRACT FROM AUTHOR]

A mathematical model for the quantitative analysis of the interaction between cancer cells and cell-mediated immune system with two discrete-time delays, considering the role of antibodies, is studied in this paper. The model is analyzed both analytically and numerically to understand the dynamics of interaction delay and proliferation enhancement effect delay in the eradication of cancer. Hopf bifurcation occurs when one-time delay crosses the critical value in the absence of the other. It is also observed that as we increase any of the delays, it will increase the cancer burden. The analysis shows that a cancer-free state cannot be obtained solely by the killing rate of cytotoxic T-lymphocytes, but humoral response in combination with cell-mediated immune responses plays an important role to eradicate cancer. [ABSTRACT FROM AUTHOR]

HIV and HTLV-I are two retroviruses that infect the CD 4 + T cells. HIV causes acquired immunodeficiency syndrome, while HTLV-I is the causative agent for adult T-cell leukemia and HTLV-I-associated myelopathy/tropical spastic paraparesis. It is not surprising that a mono-infected patient with one of these viruses can be exposure to co-infect with the other virus since they share the same way of transmissions between individuals, through direct contact with certain contaminated body fluids. Mathematical modeling and analysis of HIV and HTLV-I mono-infections have received considerable attention during the last decades. However, the dynamics of HIV/HTLV-I co-infection has not been formulated. In the present paper, we formulate a new HIV/HTLV-I co-infection model with cytotoxic T lymphocytes (CTLs) immune response. The model describes the interaction between susceptible CD 4 + T cells, HIV-infected cells, Tax-expressing HTLV-infected cells, free HIV particles, HIV-specific CTLs and HTLV-specific CTLs. The HIV can spread by virus-to-cell and cell-to-cell transmissions, while the HTLV-I can only spread via cell-to-cell transmission. The well-posedness of the model is established by showing that the solutions of the model are nonnegative and bounded. We derive the threshold parameters which govern the existence and stability of all equilibria of the model. We prove the global asymptotic stability of all equilibria by utilizing Lyapunov function and applying Lyapunov–LaSalle asymptotic stability theorem. We present numerical simulations to illustrate the effectiveness of our main results. In addition, we discuss the effect of HTLV-I infection on the HIV-infected patients and vice versa. [ABSTRACT FROM AUTHOR]

In the literature, several mathematical models have been formulated and developed to describe the within-host dynamics of either human immunodeficiency virus (HIV) or human T-lymphotropic virus type I (HTLV-I) monoinfections. In this paper, we formulate and analyze a novel within-host dynamics model of HTLV-HIV coinfection taking into consideration the response of cytotoxic T lymphocytes (CTLs). The uninfected CD 4 + T cells can be infected via HIV by two mechanisms, free-to-cell and infected-to-cell. On the other hand, the HTLV-I has two modes for transmission, (i) horizontal, via direct infected-to-cell touch, and (ii) vertical, by mitotic division of active HTLV-infected cells. It is well known that the intracellular time delays play an important role in within-host virus dynamics. In this work, we consider six types of distributed-time delays. We investigate the fundamental properties of solutions. Then, we calculate the steady states of the model in terms of threshold parameters. Moreover, we study the global stability of the steady states by using the Lyapunov method. We conduct numerical simulations to illustrate and support our theoretical results. In addition, we discuss the effect of multiple time delays on stability of the steady states of the system. [ABSTRACT FROM AUTHOR]

Immunotherapy is considered as an effective method for cancer treatment owing to the induction of specific and long-lasting anti-cancer effects. Immunotherapeutic strategies have shown significant success in human malignancies, particularly in prostate cancer (PCa), a major global health issue regarding its high metastatic rates. In fact, the first cancer vaccine approved by FDA was Provenge, which has been successfully used for treatment of PCa. Despite the remarkable success of cancer immunotherapy in PCa, many of the developed immunotherapy methods show poor therapeutic outcomes. Immunosuppression in tumor microenvironment (TME) induced by non-functional T cells (CD4+ and CD8+), tolerogenic dendritic cells (DCs), and regulatory T cells, has been reported to be the main obstacle to the effectiveness of anti-tumor immune responses induced by an immunotherapy method. The present review particularly focuses on the latest findings of the immune checkpoints (ICPs), including CTLA-4, PD-1, PD-L1, LAG-3, OX40, B7-H3, 4-1BB, VISTA, TIM-3, and ICOS; these checkpoints are able to have immune modulatory effects on the TME of PCa. This paper further discusses different approaches in ICPs targeting therapy and summarizes the latest advances in the clinical application of ICP-targeted therapy as monotherapy or in combination with other cancer therapy modalities in PCa. [ABSTRACT FROM AUTHOR]

This paper proposes and analyzes a CTL-mediated HIV infection model. The model describes the interaction between healthy CD4+T cells, silent infected cells, active infected cells, free HIV particles, and cytotoxic T lymphocytes (CTLs). The healthy CD4+T cells can be infected when contacted by one of the following: (i) free HIV particles, (ii) silent infected cells, and (iii) active infected cells. The incidence rates of the healthy CD4+T cells with free HIV particles, silent infected cells, and active infected cells are given by general functions. Moreover, the production/proliferation and removal/death rates of all compartments are represented by general functions. The model is an improvement of the existing HIV infection models which have neglected the incidence between the silent infected cells and healthy CD4+T cells. We first show that the model is well posed. The proposed model has three equilibria and their existence is governed by derived two threshold parameters: the basic HIV reproduction number ℜ 0 and the HIV-specific CTL-mediated immunity reproduction number ℜ 1 . Under a set of conditions on the general functions and the parameters ℜ 0 and ℜ 1 , we have proven the global asymptotic stability of all equilibria by using Lyapunov method. We have illustrated the theoretical results via numerical simulations. We have studied the effect of cell-to-cell (CTC) transmission on the dynamical behavior of the system. We have shown that inclusion of CTC transmission decreases the concentration of healthy CD4+T cells and increases the concentrations of infected cells and free HIV particles. [ABSTRACT FROM AUTHOR]

In this paper, we study the asymptotic and stability dynamics of a chemotaxis model in volume filling constraints on HIV-1-incorporating cytotoxic T lymphocytes (CTLs) cells in defense mechanism against the virus infection. The system of uninfected CD 4 + T -cells, infected and CTL defense cells is globally well-defined in Ω × (0 , ∞) , with uninfected CD 4 + T and CTL cells remaining bounded, while the HIV-1-activated cells decay to the null state at time t = ∞ . Routh–Hurwitz criteria yields asymptotical stability of the system, if the CTL threshold value is sufficiently large with CTL decay small, and instability otherwise. In control theory, it is implied that a bounded control yields the system not completely controllable, but bounded input-bounded output stable (b.i.b.o.-stable) with stabilizability and detectability not guaranteed. If guaranteed, the system is asymptotically stable if and only if it is b.i.b.o.-stable. In addition, numerical simulation results of the model are provided. [ABSTRACT FROM AUTHOR]

In this paper, a mathematical model is formulated to investigate the dynamics of HIV infection. The model incorporates two routes of infection (namely cell-to-cell transmission and virus-to-cell infection), two types of adaptive immune responses (i.e., cellular and antibody immune response) and two intracellular delays (viz., the eclipse phase and virus production period). By constructing Lyapunov functionals, we show that the global dynamics of the model can be explicitly determined by five reproduction numbers. Using the uncertainty and sensitivity analyses, we obtain the mean values and standard deviation of the five reproduction numbers and find that the reproduction numbers are most sensitive to the death rate of infected cells, viral clearance rate and immune parameters. We further compare four related HIV models and show that cell-to-cell transmission, immune responses and time delays can substantially affect the dynamical behavior of the system. Specifically, cell-to-cell transmission increases the concentration of infected cells. Inclusion of cytotoxic T lymphocyte and virus production delay can significantly reduce the viral load and infected cell concentration, and generate a higher level of uninfected CD4+ T cells. The analytical and numerical results may help to improve the understanding of HIV dynamics. [ABSTRACT FROM AUTHOR]

This paper studies the global dynamics of a general diffusive hepatitis B virus (HBV) infection model. The model includes both enveloped viruses and DNA containing capsids. Two immune responses are recruited to attack the virus and infected hepatocytes. These are the cytotoxic T-lymphocytes (CTL) which kill the infected liver cells, and B cells which send antibodies to attack the virus. The non-negativity and boundedness of the solutions are discussed. The existence of spatially homogeneous equilibrium points is examined. The global stability of all possible equilibrium points is proved by choosing suitable Lyapunov functionals. Some numerical simulations are performed to enhance the theoretical results and present the behavior of solutions in space and time. [ABSTRACT FROM AUTHOR]

Yellow fever outbreaks are prevalent, particularly in endemic regions. Given the lack of an established treatment for this disease, significant attention has been directed toward managing this arbovirus. In response, we developed a multiepitope vaccine designed to elicit an immune response, utilizing advanced immunoinformatic and molecular modeling techniques. To achieve this, we predicted B- and T-cell epitopes using the sequences from all structural (E, prM, and C) and nonstructural proteins of 196 YFV strains. Through comprehensive analysis, we identified 10 cytotoxic T-lymphocyte (CTL) and 5T-helper (Th) epitopes that exhibited overlap with B-lymphocyte epitopes. These epitopes were further evaluated for their affinity to a wide range of human leukocyte antigen system alleles and were rigorously tested for antigenicity, immunogenicity, allergenicity, toxicity, and conservation. These epitopes were linked to an adjuvant (β -defensin) and to each other using ligands, resulting in a vaccine sequence with appropriate physicochemical properties. The 3D structure of this sequence was created, improved, and quality checked; then it was anchored to the Toll-like receptor. Molecular Dynamics and Quantum Mechanics/Molecular Mechanics simulations were employed to enhance the accuracy of docking calculations, with the QM portion of the simulations carried out utilizing the density functional theory formalism. Moreover, the inoculation model was able to provide an optimal codon sequence that was inserted into the pET-28a(+) vector for in silico cloning and could even stimulate highly relevant humoral and cellular immunological responses. Overall, these results suggest that the designed multi-epitope vaccine can serve as prophylaxis against the yellow fever virus. [ABSTRACT FROM AUTHOR]

Antimicrobial peptides are essential components of innate defense mechanisms and make promising candidates for novel anti-infective agents. The advantages of these peptides in clinical applications include their potential for broad-spectrum and rapid bactericidal activities, and low propensity for resistance development, whereas possible disadvantages include their high cost, limited stability, and unknown toxicology and pharmacokinetics. Granulysin (Gr) is a cytolytic and proinflammatory molecule expressed by activated human cytotoxic T lymphocytes and natural killer (NK) cells. This paper aims to study bacteriostatic and bactericidal activity against Mycobacterium tuberculosis by synthetic analogues of human Gr between 12 and 26 amino acids (AA) and their acyl derivatives. Considering results of previous studies, five new peptides were designed: a cyclic of 20 AA (Gr-SL1); one of 21 AA (linear) (Gr-SL2), another of 12 AA (cyclic) (Gr-SL3) and two lipopeptides (Gr-SL3-lauric and Gr-SL3-palmitic). Peptides were manually synthesized as C-terminal carboxamides by the solid-phase method following Fmoc chemistry. Gr synthetic analogues were purified by reverse phase HPLC and analyzed by analytical C18RP-HPLC and Maldi Tof. The antimycobacterial activity of synthesized Gr analogues was assessed using a microdilution susceptibility test as described previously. Although peptides studied here had neither higher antimycobacterial activity nor lower toxicity than analogs of human Gr previously evaluated, fresh knowledge concerning the influence of acylation and structural aspects analyzed will optimize the design of novel peptides combining the most favorable aspects for the maintenance of antimycobacterial activity with minimum toxicity. [ABSTRACT FROM AUTHOR]

In this paper, we construct an infection-age model to study the interaction between viruses and the immune system within the host. In the model, the mortality rate of infected cells, the rate that cytotoxic T lymphocytes (CTL) kill infected cells, the rate that infected cells produce new virus, and the CTL proliferate rate may depend on the infection-age. The basic reproduction number and the threshold for the existence of steady states are obtained. Local stability of both the infection-free and infection steady states is studied by analyzing the linearized systems. Global stability of the infection-free steady state is obtained by investigating a renewal integral equation and global stability of the infection steady state is obtained by constructing a Liapunov functional. Numerical simulations are presented to verify the theoretical results. [ABSTRACT FROM AUTHOR]

Celiac disease is a chronic inflammatory condition of the small intestine caused by aberrant adaptive immune response to gluten protein from wheat and related cereal plants. Over 90% of celiac disease patients carry the HLA-DQ2.5 allotype and HLA-DQ2.5 presents gluten peptides to gluten-reactive CD4+ T cells in celiac disease patients. A large number of HLA-DQ2.5-restricted gluten T cell epitopes have been identified over the years. These epitopes are in general proline-rich and contain at least one glutamic acid residue that is generated from glutamine in the native gluten protein by deamidation. The deamidation is mediated by the enzyme transglutaminase 2 (TG2). It has been shown that the same T cell could recognize several different HLA-DQ2.5-restricted gluten T cell epitopes due to sequence similarities. In this paper, we demonstrate that three T cell clones derived from duodenal biopsies of different celiac disease patients are able to respond to at least five different gluten T cell epitopes within the DQ2.5-glia-γ4 epitope family, including two novel epitopes. [ABSTRACT FROM AUTHOR]

In this paper, a diffusive and delayed virus dynamics model with Crowley-Martin incidence function and CTL immune response is investigated. By constructing the Lyapunov functionals, the threshold conditions on the global stability of the infection-free, immune-free and interior equilibria are established if the space is assumed to be homogeneous. We show that the infection-free equilibrium is globally asymptotically stable if the basic reproductive number $R_{0}\leq1$ ; the immune-free equilibrium is globally asymptotically stable if the immune reproduction number and the basic reproduction number satisfy $R_{1}\leq1< R_{0}$ ; the interior equilibrium is globally asymptotically stable if $R_{1}>1$ . [ABSTRACT FROM AUTHOR]

The Ataxia telangiectasia and Rad3-related (ATR) inhibitor ceralasertib in combination with the PD-L1 antibody durvalumab demonstrated encouraging clinical benefit in melanoma and lung cancer patients who progressed on immunotherapy. Here we show that modelling of intermittent ceralasertib treatment in mouse tumor models reveals CD8+ T-cell dependent antitumor activity, which is separate from the effects on tumor cells. Ceralasertib suppresses proliferating CD8+ T-cells on treatment which is rapidly reversed off-treatment. Ceralasertib causes up-regulation of type I interferon (IFNI) pathway in cancer patients and in tumor-bearing mice. IFNI is experimentally found to be a major mediator of antitumor activity of ceralasertib in combination with PD-L1 antibody. Improvement of T-cell function after ceralasertib treatment is linked to changes in myeloid cells in the tumor microenvironment. IFNI also promotes anti-proliferative effects of ceralasertib on tumor cells. Here, we report that broad immunomodulatory changes following intermittent ATR inhibition underpins the clinical therapeutic benefit and indicates its wider impact on antitumor immunity. The ATR inhibitor ceralasertib has shown clinical activity in combination with immune-checkpoint inhibitors in several cancer types. Here the authors report the anti-tumor activity and the immunomodulatory changes, dependent on up-regulation of type I interferon pathway, following intermittent ATR inhibition in preclinical cancer models. [ABSTRACT FROM AUTHOR]

The interactions between tumor and immune cells along the course of breast cancer progression remain largely unknown. Here, we extensively characterize multiple sequential and parallel multiregion tumor and blood specimens of an index patient and a cohort of metastatic triple-negative breast cancers. We demonstrate that a continuous increase in tumor genomic heterogeneity and distinct molecular clocks correlated with resistance to treatment, eventually allowing tumors to escape from immune control. TCR repertoire loses diversity over time, leading to convergent evolution as breast cancer progresses. Although mixed populations of effector memory and cytotoxic single T cells coexist in the peripheral blood, defects in the antigen presentation machinery coupled with subdued T cell recruitment into metastases are observed, indicating a potent immune avoidance microenvironment not compatible with an effective antitumor response in lethal metastatic disease. Our results demonstrate that the immune responses against cancer are not static, but rather follow dynamic processes that match cancer genomic progression, illustrating the complex nature of tumor and immune cell interactions. Immune response during breast cancer progression remains to be explored. Here, the characterisation of sequential and parallel multiregion samples of an index patient and a cohort of metastatic triple-negative breast cancers reveals convergent immune evasion mechanisms and an increase in tumor genomic heterogeneity. [ABSTRACT FROM AUTHOR]

Acquired resistance to immunotherapy remains a critical yet incompletely understood biological mechanism. Here, using a mouse model of pancreatic ductal adenocarcinoma (PDAC) to study tumor relapse following immunotherapy-induced responses, we find that resistance is reproducibly associated with an epithelial-to-mesenchymal transition (EMT), with EMT-transcription factors ZEB1 and SNAIL functioning as master genetic and epigenetic regulators of this effect. Acquired resistance in this model is not due to immunosuppression in the tumor immune microenvironment, disruptions in the antigen presentation machinery, or altered expression of immune checkpoints. Rather, resistance is due to a tumor cell-intrinsic defect in T-cell killing. Molecularly, EMT leads to the epigenetic and transcriptional silencing of interferon regulatory factor 6 (Irf6), rendering tumor cells less sensitive to the pro-apoptotic effects of TNF-α. These findings indicate that acquired resistance to immunotherapy may be mediated by programs distinct from those governing primary resistance, including plasticity programs that render tumor cells impervious to T-cell killing. Acquired resistance to immune checkpoint inhibitors represents an important clinical challenge. Here, in a pancreatic ductal adenocarcinoma model of acquired resistance to immunotherapy, the authors show that plasticity-induced repression of Irf6 is associated with tumor cell-intrinsic resistance to cytotoxic T-cell activity. [ABSTRACT FROM AUTHOR]

Mechanical force contributes to perforin pore formation at immune synapses, thus facilitating the cytotoxic T lymphocytes (CTL)-mediated killing of tumor cells in a unidirectional fashion. How such mechanical cues affect CTL evasion of perforin-mediated autolysis remains unclear. Here we show that activated CTLs use their softness to evade perforin-mediated autolysis, which, however, is shared by T leukemic cells to evade CTL killing. Downregulation of filamin A is identified to induce softness via ZAP70-mediated YAP Y357 phosphorylation and activation. Despite the requirements of YAP in both cell types for softness induction, CTLs are more resistant to YAP inhibitors than malignant T cells, potentially due to the higher expression of the drug-resistant transporter, MDR1, in CTLs. As a result, moderate inhibition of YAP stiffens malignant T cells but spares CTLs, thus allowing CTLs to cytolyze malignant cells without autolysis. Our findings thus hint a mechanical force-based immunotherapeutic strategy against T cell leukemia. Cell softness protects cytotoxic T lymphocytes (CTL) from autolysis by own soluble factors such as perforin secreted for killing target cells. Here the authors show that softness can be induced by YAP activation, and that T leukemic cells are more sensitive to YAP inhibition than CTLs, thereby hinting YAP inhibitors as a potential therapy for T leukemia. [ABSTRACT FROM AUTHOR]

Engagement of the T cell receptor (TCR) triggers molecular reprogramming leading to the acquisition of specialized effector functions by CD4 helper and CD8 cytotoxic T cells. While transcription factors, chemokines, and cytokines are known drivers in this process, the temporal proteomic and transcriptomic changes that regulate different stages of human primary T cell activation remain to be elucidated. Here, we report an integrative temporal proteomic and transcriptomic analysis of primary human CD4 and CD8 T cells following ex vivo stimulation with anti-CD3/CD28 beads, which revealed major transcriptome-proteome uncoupling. The early activation phase in both CD4 and CD8 T cells was associated with transient downregulation of the mRNA transcripts and protein of the central glucose transport GLUT1. In the proliferation phase, CD4 and CD8 T cells became transcriptionally more divergent while their proteome became more similar. In addition to the kinetics of proteome-transcriptome correlation, this study unveils selective transcriptional and translational metabolic reprogramming governing CD4 and CD8 T cell responses to TCR stimulation. This temporal transcriptome/proteome map of human T cell activation provides a reference map exploitable for future discovery of biomarkers and candidates targeting T cell responses. [ABSTRACT FROM AUTHOR]

Immunotherapy with immune checkpoint blockade (ICB) for glioblastoma (GBM) is promising but its clinical efficacy is seriously challenged by the blood-tumor barrier (BTB) and immunosuppressive tumor microenvironment. Here, anti-programmed death-ligand 1 antibodies (aPD-L1) are loaded into a redox-responsive micelle and the ICB efficacy is further amplified by paclitaxel (PTX)-induced immunogenic cell death (ICD) via a co-encapsulation approach for the reinvigoration of local anti-GBM immune responses. Consequently, the micelles cross the BTB and are retained in the reductive tumor microenvironment without altering the bioactivity of aPD-L1. The ICB efficacy is enhanced by the aPD-L1 and PTX combination with suppression of primary and recurrent GBM, accumulation of cytotoxic T lymphocytes, and induction of long-lasting immunological memory in the orthotopic GBM-bearing mice. The co-encapsulation approach facilitating efficient antibody delivery and combining with chemotherapeutic agent-induced ICD demonstrate that the chemo-immunotherapy might reprogram local immunity to empower immunotherapy against GBM. Immune checkpoint blockade-based immunotherapy has shown limited efficacy in patients with glioblastoma (GBM). Here the authors describe the design of redox-responsive micelles for increasing the delivery of paclitaxel and anti-PD-L1 in the brain, showing improved anti-tumor immune response in preclinical GBM models. [ABSTRACT FROM AUTHOR]

Invariant natural killer T (iNKT) cells, a unique T cell population, lend themselves for use as adoptive therapy due to diverse roles in orchestrating immune responses. Originally developed for use in cancer, agenT-797 is a donor-unrestricted allogeneic ex vivo expanded iNKT cell therapy. We conducted an open-label study in virally induced acute respiratory distress syndrome (ARDS) caused by the severe acute respiratory syndrome-2 virus (trial registration NCT04582201). Here we show that agenT-797 rescues exhausted T cells and rapidly activates both innate and adaptive immunity. In 21 ventilated patients including 5 individuals receiving veno-venous extracorporeal membrane oxygenation (VV-ECMO), there are no dose-limiting toxicities. We observe an anti-inflammatory systemic cytokine response and infused iNKT cells are persistent during follow-up, inducing only transient donor-specific antibodies. Clinical signals of associated survival and prevention of secondary infections are evident. Cellular therapy using off-the-shelf iNKT cells is safe, can be rapidly scaled and is associated with an anti-inflammatory response. The safety and therapeutic potential of iNKT cells across diseases including infections and cancer, warrants randomized-controlled trials. Invariant natural killer T (iNKT) cells recognize abnormal cells, but their T cell receptor is not variable and kill cancerous or infected target cells without MHC I restriction. Here, the authors show that in a clinical trial, donor-unrestricted allogeneic iNKT cells could be safely administered to human COVID-19 patients suffering from acute respiratory distress syndrome and trigger an anti-inflammatory response. [ABSTRACT FROM AUTHOR]

Despite promising preclinical and earlier clinical data, a recent phase III trial on the anti-β7 integrin antibody etrolizumab in Crohn's disease (CD) did not reach its primary endpoint. The mechanisms leading to this outcome are not well understood. Here we characterize the β7+ T cell compartment from patients with CD in comparison to cells from individuals without inflammatory bowel disease. By flow cytometric, transcriptomic and functional profiling of circulating T cells, we find that triple-integrin-expressing (α4+β7+β1hi) T cells have the potential to home to the gut despite α4β7 blockade and have a specific cytotoxic signature. A subset of triple-integrin-expressing cells readily acquires αE expression and could be co-stimulated via E-Cadherin-αEβ7 interactions in vitro. Etrolizumab-s fails to block such αEβ7 signalling at high levels of T cell stimulation. Consistently, in CD patients treated with etrolizumab, T cell activation correlates with cytotoxic signatures. Collectively, our findings might add one important piece to the puzzle to explain phase III trial results with etrolizumab, while they also highlight that αEβ7 remains an interesting target for future therapeutic approaches in inflammatory bowel disease. The clinical success of anti- αEβ7 antibody Etrolizumab for Crohn's disease is less than what is expected based on proof-of-concept studies. Here authors show, by characterization of T cells from Etrolizumab-treated patients, in vitro functional assays and reanalysis of public single cell datasets on Etrolizumab-treated patients, that at high level of T cell activation, which characterises T cells in Crohn's disease, E-Cadherin-αEβ7 interactions become resistant to Etrolizumab inhibition. [ABSTRACT FROM AUTHOR]

Background and Objective: Immune checkpoint inhibitors (ICIs) such as programmed cell death protein 1 (PD-1) and cytotoxic T-lymphocyte antigen 4 (CTLA-4) inhibitors have greatly improved cancer treatment. However, they are associated with immune-related adverse events, including autoimmune diseases (ADs) owing to their immune enhancement effect. As there are few comprehensive studies of ADs by ICIs, it is necessary to analyze the period information of drug-induced ADs. We also assumed that the temporal information may be useful to estimate the similarity of the pathogenic mechanism between spontaneous and ICI-induced ADs. Methods: A period analysis including the Weibull analysis was performed on ICI-induced ADs using the Japanese Adverse Drug Event Report (JADER) database. For evaluating the similarity of spontaneous and ICI-induced ADs, a hierarchical cluster analysis was conducted to compare the different onset-time ranges. Results: Type 1 diabetes mellitus, autoimmune colitis, and pemphigoid occurred earlier with CTLA-4 inhibitors (median: 46, 29.5 and 28 days, respectively) than with PD-1 inhibitors (> 130 days). Myasthenia gravis had a median time to onset of approximately 1 month, and the risk of onset would increase over time in ipilimumab combination therapy. This result reveals ADs that require attention. Using cluster analysis, we estimated six clusters with different patterns of onset times. Based on these results and a detailed previous research survey, the possible pathogenesis of drug-induced ADs was also discussed. Conclusions: This paper describes risk profiles with temporal information of ICI-induced ADs and proposes certain indicators for deciphering the mechanism of AD onset. [ABSTRACT FROM AUTHOR]

Tumour dendritic cells (DCs) internalise antigen and upregulate CCR7, which directs their migration to tumour-draining lymph nodes (dLN). CCR7 expression is coupled to an activation programme enriched in regulatory molecule expression, including PD-L1. However, the spatio-temporal dynamics of CCR7+ DCs in anti-tumour immune responses remain unclear. Here, we use photoconvertible mice to precisely track DC migration. We report that CCR7+ DCs are the dominant DC population that migrate to the dLN, but a subset remains tumour-resident despite CCR7 expression. These tumour-retained CCR7+ DCs are phenotypically and transcriptionally distinct from their dLN counterparts and heterogeneous. Moreover, they progressively downregulate the expression of antigen presentation and pro-inflammatory transcripts with more prolonged tumour dwell-time. Tumour-residing CCR7+ DCs co-localise with PD-1+CD8+ T cells in human and murine solid tumours, and following anti-PD-L1 treatment, upregulate stimulatory molecules including OX40L, thereby augmenting anti-tumour cytolytic activity. Altogether, these data uncover previously unappreciated heterogeneity in CCR7+ DCs that may underpin a variable capacity to support intratumoural cytotoxic T cells. Recognition of tumour antigen induces dendritic cell activation and migration to the lymph node. Here, the authors use photoconvertible mice to demonstrate that some activated dendritic cells are retained in tumours and gradually lose function, but their ability to support local anti-tumour responses can be augmented by anti-PD-L1 blockade. [ABSTRACT FROM AUTHOR]

There is an unmet need for antigen delivery systems that elicit efficient T cell priming to prevent infectious diseases or for treatment of cancers. Here, we explored the immunogenic potential of biologically assembled biopolymer particles (BPs) that have been bioengineered to display the antigenic MHC I and MHC II epitopes of model antigen ovalbumin (OVA). Purified dendritic cells (DCs) captured BP-OVA and presented the associated antigenic epitopes to CD4+ T cells and CD8+ T cells. Vaccination with BP-OVA in the absence of adjuvant elicited antigen presentation to OVA-specific CD8+ and CD4+ T cells and cross-primed effective cytotoxic T lymphocyte (CTL) killers. BP-OVA induction of CTL killing did not require CD4+ T cell help, with active CTLs generated in BP-OVA vaccinated I-Ab−/− and CD40−/− mice. In contrast, IL-15 and type I IFN were required, with abrogated CTL activity in vaccinated IL-15−/− and IFNAR1−/− mice. cDC1 and/or CD103+ DCs were not essential for BP-OVA specific CTL with immunization eliciting responses in Batf3−/− mice. Poly I:C, but not LPS or CpG, co-administered as an adjuvant with BP-OVA boosted CTL responses. Finally, vaccination with BP-OVA protected against B16-OVA melanoma and Eμ-myc-GFP-OVA lymphoma inoculation. In summary, we have demonstrated that epitope-displaying BPs represent an antigen delivery platform exhibiting a unique mechanism to effectively engage T cell immune responses. [ABSTRACT FROM AUTHOR]

Mutant KRAS (KRASMUT) is often exploited by cancers to shape tumor immunity, but the underlying mechanisms are not fully understood. Here we report that tumor-specific cytotoxic T lymphocytes (CTLs) from KRASMUT cancers are sensitive to activation-induced cell death (AICD). circATXN7, an NF-κB-interacting circular RNA, governs T cell sensitivity to AICD by inactivating NF-κB. Mechanistically, histone lactylation derived from KRASMUT tumor cell-produced lactic acid directly activates transcription of circATXN7, which binds to NF-κB p65 subunit and masks the p65 nuclear localization signal motif, thereby sequestering it in the cytoplasm. Clinically, circATXN7 upregulation in tumor-specific CTLs correlates with adverse clinical outcomes and immunotherapeutic resistance. Genetic ablation of circAtxn7 in CD8+ T cells leads to mutant-selective tumor inhibition, while also increases anti-PD1 efficacy in multiple tumor models in female mice. Furthermore, targeting circATXN7 in adoptively transferred tumor-reactive CTLs improves their antitumor activities. These findings provide insight into how lymphocyte-expressed circRNAs contribute to T-cell fate decisions and anticancer immunotherapies. Oncogenic KRAS mutations can dictate the formation of an immune-suppressive tumor microenvironment. Here the authors report that, in KRAS mutant colorectal cancer, the upregulation of circATXN7 in tumor-specific cytotoxic T lymphocytes is associated with increased sensitivity to activation-induced cell death and resistance to immunotherapy." [ABSTRACT FROM AUTHOR]

T-cell cytotoxic function relies on the cooperation between the highly specific but poorly adhesive T-cell receptor (TCR) and the integrin LFA-1. How LFA-1-mediated adhesion may scale with TCR stimulation strength is ill-defined. Here, we show that LFA-1 conformation activation scales with TCR stimulation to calibrate human T-cell cytotoxicity. Super-resolution microscopy analysis reveals that >1000 LFA-1 nanoclusters provide a discretized platform at the immunological synapse to translate TCR engagement and density of the LFA-1 ligand ICAM-1 into graded adhesion. Indeed, the number of high-affinity conformation LFA-1 nanoclusters increases as a function of TCR triggering strength. Blockade of LFA-1 conformational activation impairs adhesion to target cells and killing. However, it occurs at a lower TCR stimulation threshold than lytic granule exocytosis implying that it licenses, rather than directly controls, the killing decision. We conclude that the organization of LFA-1 into nanoclusters provides a calibrated system to adjust T-cell killing to the antigen stimulation strength. CD8+ T cell activation involves cooperation between the T cell receptor and the integrin LFA-1. Here authors show how LFA-1 nanoclusters participate in the calibration of TCR stimulation strength and activation of cytotoxic function in CD8+ T cells. [ABSTRACT FROM AUTHOR]

Classic Hodgkin lymphoma (cHL) is characterized by a rich immune microenvironment as the main tumor component. It involves a broad range of cell populations, which are largely unexplored, even though they are known to be essential for growth and survival of Hodgkin and Reed–Sternberg cells. We profiled the gene expression of 25 FFPE cHL samples using NanoString technology and resolved their microenvironment compositions using cell-deconvolution tools, thereby generating patient-specific signatures. The results confirm individual immune fingerprints and recognize multiple clusters enriched in refractory patients, highlighting the relevance of: (1) the composition of immune cells and their functional status, including myeloid cell populations (M1-like, M2-like, plasmacytoid dendritic cells, myeloid-derived suppressor cells, etc.), CD4-positive T cells (exhausted, regulatory, Th17, etc.), cytotoxic CD8 T and natural killer cells; (2) the balance between inflammatory signatures (such as IL6, TNF, IFN-γ/TGF-β) and MHC-I/MHC-II molecules; and (3) several cells, pathways and genes related to the stroma and extracellular matrix remodeling. A validation model combining relevant immune and stromal signatures identifies patients with unfavorable outcomes, producing the same results in an independent cHL series. Our results reveal the heterogeneity of immune responses among patients, confirm previous findings, and identify new functional phenotypes of prognostic and predictive utility. [ABSTRACT FROM AUTHOR]

Adipose tissue invariant natural killer T (iNKT) cells are a crucial cell type for adipose tissue homeostasis in obese animals. However, heterogeneity of adipose iNKT cells and their function in adipocyte turnover are not thoroughly understood. Here, we investigate transcriptional heterogeneity in adipose iNKT cells and their hierarchy using single-cell RNA sequencing in lean and obese mice. We report that distinct subpopulations of adipose iNKT cells modulate adipose tissue homeostasis through adipocyte death and birth. We identify KLRG1+ iNKT cells as a unique iNKT cell subpopulation in adipose tissue. Adoptive transfer experiments showed that KLRG1+ iNKT cells are selectively generated within adipose tissue microenvironment and differentiate into a CX3CR1+ cytotoxic subpopulation in obese mice. In addition, CX3CR1+ iNKT cells specifically kill enlarged and inflamed adipocytes and recruit macrophages through CCL5. Furthermore, adipose iNKT17 cells have the potential to secrete AREG, and AREG is involved in stimulating adipose stem cell proliferation. Collectively, our data suggest that each adipose iNKT cell subpopulation plays key roles in the control of adipocyte turnover via interaction with adipocytes, adipose stem cells, and macrophages in adipose tissue. Invariant natural killer T (iNKT) cells have recently been reported to play a key role in adipose tissue homeostasis. Here, the authors show that adipose tissue iNKT cells mediate immune responses that control adipocyte turnover in mice. [ABSTRACT FROM AUTHOR]

Immunotherapy remains more effective for hematologic tumors than for solid tumors. One of the main challenges to immunotherapy of solid tumors is the immunosuppressive microenvironment these tumors generate, which limits the cytotoxic capabilities of immune effector cells (e.g., cytotoxic T and natural killer cells). This microenvironment is characterized by hypoxia, nutrient starvation, accumulated waste products, and acidic pH. Tumor-hijacked cells, such as fibroblasts, macrophages, and T regulatory cells, also contribute to this inhospitable microenvironment for immune cells by secreting immunosuppressive cytokines that suppress the antitumor immune response and lead to immune evasion. Thus, there is a strong interest in developing new drugs and cell formulations that modulate the tumor microenvironment and reduce tumor cell immune evasion. Microphysiological systems (MPSs) are versatile tools that may accelerate the development and evaluation of these therapies, although specific examples showcasing the potential of MPSs remain rare. Advances in microtechnologies have led to the development of sophisticated microfluidic devices used to recapitulate tumor complexity. The resulting models, also known as microphysiological systems (MPSs), are versatile tools with which to decipher the molecular mechanisms driving immune cell antitumor cytotoxicity, immune cell exhaustion, and immune cell exclusion and to evaluate new targeted immunotherapies. Here, we review existing microphysiological platforms to study immuno-oncological applications and discuss challenges and opportunities in the field. [ABSTRACT FROM AUTHOR]

Computational deconvolution with single-cell RNA sequencing data as reference is pivotal to interpreting spatial transcriptomics data, but the current methods are limited to cell-type resolution. Here we present Redeconve, an algorithm to deconvolute spatial transcriptomics data at single-cell resolution, enabling interpretation of spatial transcriptomics data with thousands of nuanced cell states. We benchmark Redeconve with the state-of-the-art algorithms on diverse spatial transcriptomics platforms and datasets and demonstrate the superiority of Redeconve in terms of accuracy, resolution, robustness, and speed. Application to a human pancreatic cancer dataset reveals cancer-clone-specific T cell infiltration, and application to lymph node samples identifies differential cytotoxic T cells between IgA+ and IgG+ spots, providing novel insights into tumor immunology and the regulatory mechanisms underlying antibody class switch. Computational deconvolution with single-cell RNA sequencing data as a reference is pivotal for interpreting spatial transcriptomics data. Here, authors present Redeconve, which improves the resolution by more than 100-fold with higher accuracy and speed. [ABSTRACT FROM AUTHOR]

Invariant natural killer T (NKT) cell subsets are defined based on their cytokine-production profiles and transcription factors. Their distribution is different in C57BL/6 (B6) and BALB/c mice, with a bias for NKT1 and NKT2/NKT17 subsets, respectively. Here, we show that the non-classical class I-like major histocompatibility complex CD1 molecules CD1d2, expressed in BALB/c and not in B6 mice, could not account for this difference. We find however that NKT cell subset distribution is intrinsic to bone marrow derived NKT cells, regardless of syngeneic CD1d-ligand recognition, and that multiple intrinsic factors are likely involved. Finally, we find that CD1d expression levels in combination with T cell antigen receptor signal strength could also influence NKT cell distribution and function. Overall, this study indicates that CD1d-mediated TCR signals and other intrinsic signals integrate to influence strain-specific NKT cell differentiation programs and subset distributions. Invariant natural killer T (NKT) cells are defined into subset based on transcription expression and cytokine production, but differences in the subset distributions of these cells are seen between inbred mouse strains. Here the authors show that CD1d mediated TCR signals along with intrinsic signals impact this strain specific difference in the composition of the NKT cell compartment. [ABSTRACT FROM AUTHOR]

Epacadostat (EPA), the most advanced IDO1 inhibitor, in combination with PD-1 checkpoint inhibitor, has failed in a recent Phase III clinical trial for treating metastatic melanoma. Here we report an EPA nanovesicle therapeutic platform (Epacasome) based on chemically attaching EPA to sphingomyelin via an oxime-ester bond highly responsive to hydrolase cleavage. Via clathrin-mediated endocytosis, Epacasome displays higher cellular uptake and enhances IDO1 inhibition and T cell proliferation compared to free EPA. Epacasome shows improved pharmacokinetics and tumour accumulation with efficient intratumoural drug release and deep tumour penetration. Additionally, it outperforms free EPA for anticancer efficacy, potentiating PD-1 blockade with boosted cytotoxic T lymphocytes (CTLs) and reduced regulatory T cells and myeloid-derived suppressor cells responses in a B16-F10 melanoma model in female mice. By co-encapsulating immunogenic dacarbazine, Epacasome further enhances anti-tumor effects and immune responses through the upregulation of NKG2D-mediated CTLs and natural killer cells responses particularly when combined with the PD-1 inhibitor in the late-stage metastatic B16-F10-Luc2 model in female mice. Furthermore, this combination prevents tumour recurrence and prolongs mouse survival in a clinically relevant, post-surgical melanoma model in female mice. Epacasome demonstrates potential to synergize with PD-1 blockade for improved response to melanoma immunotherapy. Epacadostat is a selective IDO1 inhibitor shown to promote anti-tumor immune responses in preclinical models, however it has failed in a Phase III clinical trial for treating metastatic melanoma. Here the authors design a sphingomyelin-derived nanovesicle system for epacadostat delivery with improved pharmacokinetics and anti-tumor activity when combined with a PD-1 inhibitor in melanoma preclinical models. [ABSTRACT FROM AUTHOR]

Single cell spatial interrogation of the immune-structural interactions in COVID −19 lungs is challenging, mainly because of the marked cellular infiltrate and architecturally distorted microstructure. To address this, we develop a suite of mathematical tools to search for statistically significant co-locations amongst immune and structural cells identified using 37-plex imaging mass cytometry. This unbiased method reveals a cellular map interleaved with an inflammatory network of immature neutrophils, cytotoxic CD8 T cells, megakaryocytes and monocytes co-located with regenerating alveolar progenitors and endothelium. Of note, a highly active cluster of immature neutrophils and CD8 T cells, is found spatially linked with alveolar progenitor cells, and temporally with the diffuse alveolar damage stage. These findings offer further insights into how immune cells interact in the lungs of severe COVID-19 disease. We provide our pipeline [Spatial Omics Oxford Pipeline (SpOOx)] and visual-analytical tool, Multi-Dimensional Viewer (MDV) software, as a resource for spatial analysis. Mathematical tools can be used to help identify pathological features from images of diseased lungs. Here, the authors used mathematical tools combined with high resolution multiplex imaging mass cytometry to show an association between immature neutrophils, CD8 T cells and proliferating alveolar epithelial cells in areas of maximal alveolar damage in COVID-19 lungs. [ABSTRACT FROM AUTHOR]

The dense stroma of desmoplastic tumor limits nanotherapeutic penetration and hampers the antitumor immune response. Here, we report a denaturation-and-penetration strategy and the use of tin monosulfide nanoparticles (SnSNPs) as nano-sonosensitizers that can overcome the stromal barrier for the management of desmoplastic triple-negative breast cancer (TNBC). SnSNPs possess a narrow bandgap (1.18 eV), allowing for efficient electron (e−)-hole (h+) pair separation to generate reactive oxygen species under US activation. More importantly, SnSNPs display mild photothermal properties that can in situ denature tumor collagen and facilitate deep penetration into the tumor mass upon near-infrared irradiation. This approach significantly enhances sonodynamic therapy (SDT) by SnSNPs and boosts antitumor immunity. In mouse models of malignant TNBC and hepatocellular carcinoma (HCC), the combination of robust SDT and enhanced cytotoxic T lymphocyte infiltration achieves remarkable anti-tumor efficacy. This study presents an innovative approach to enhance SDT and antitumor immunity using the denaturation-and-penetration strategy, offering a potential combined sono-immunotherapy approach for the cancer nanomedicine field. The dense stroma of desmoplastic tumor limits nanotherapeutic penetration and hampers the antitumor immune response. Here the authors use tin monosulfide nanoparticles as nano-sonosensitizers to overcome the stromal barrier in triple negative breast cancer and improve the efficacy of sonodynamic therapy and boost antitumor immunity. [ABSTRACT FROM AUTHOR]

After activation, some invariant natural killer T (iNKT) cells are differentiated into Klrg1+ long-lived effector NKT1 cells. However, the regulation from the effector phase to the memory phase has not been elucidated. Zeb2 is a zinc finger E homeobox-binding transcription factor and is expressed in a variety of immune cells, but its function in iNKT cell differentiation remains also unknown. Here, we show that Zeb2 is dispensable for development of iNKT cells in the thymus and their maintenance in steady state peripheral tissues. After ligand stimulation, Zeb2 plays essential roles in the differentiation to and maintenance of Klrg1+ Cx3cr1+GzmA+ iNKT cell population derived from the NKT1 subset. Our results including single-cell-RNA-seq analysis indicate that Zeb2 regulates Klrg1+ long-lived iNKT cell differentiation by preventing apoptosis. Collectively, this study reveals the crucial transcriptional regulation by Zeb2 in establishment of the memory iNKT phase through driving differentiation of Klrg1+ Cx3cr1+GzmA+ iNKT population. Zeb2 is critical for the establishment of Klrg1+ long-lived effector iNKT cells from the NKT1 subset in the lungs after antigen stimulation [ABSTRACT FROM AUTHOR]

Cytokine therapy, involving interleukin-15 (IL-15), is a promising strategy for cancer immunotherapy. However, clinical application has been limited due to severe toxicity and the relatively low immune response rate, caused by wide distribution of cytokine receptors, systemic immune activation and short half-life of IL-15. Here we show that a biomimetic nanovaccine, developed to co-deliver IL-15 and an antigen/major histocompatibility complex (MHC) selectively targets IL-15 to antigen-specific cytotoxic T lymphocytes (CTL), thereby reducing off-target toxicity. The biomimetic nanovaccine is composed of cytomembrane vesicles, derived from genetically engineered dendritic cells (DC), onto which IL-15/IL-15 receptor α (IL-15Rα), tumor-associated antigenic (TAA) peptide/MHC-I, and relevant costimulatory molecules are simultaneously anchored. We demonstrate that, in contrast to conventional IL-15 therapy, the biomimetic nanovaccine with multivalent IL-15 self-transpresentation (biNV-IL-15) prolonged blood circulation of the cytokine with an 8.2-fold longer half-life than free IL-15 and improved the therapeutic window. This dual targeting strategy allows for spatiotemporal manipulation of therapeutic T cells, elicits broad spectrum antigen-specific T cell responses, and promotes cures in multiple syngeneic tumor models with minimal systemic side effects. Cancer immune therapy utilizing interleukin 15 (Il-15) is hampered by the short half-life and systemic toxic effects of the cytokine. Here authors introduce a biomimetic nanovaccine, in which Il-15 and tumor-associated antigenic peptide/MHC-I complexes are co-anchored to cell membrane vesicles of dendritic cell origin, which elicits antigen-specific T cell response leading to superior anti-tumour effect in syngeneic mouse tumour models. [ABSTRACT FROM AUTHOR]

Type 1 conventional dendritic cells (cDC1) are the most efficient cross-presenting cells that induce protective cytotoxic T cell response. However, the regulation of their homeostasis and function is incompletely understood. Here we observe a selective reduction of splenic cDC1 accompanied by excessive cell death in mice with Zeb1 deficiency in dendritic cells, rendering the mice more resistant to Listeria infection. Additionally, cDC1 from other sources of Zeb1-deficient mice display impaired cross-presentation of exogenous antigens, compromising antitumor CD8+ T cell responses. Mechanistically, Zeb1 represses the expression of microRNA-96/182 that target Cybb mRNA of NADPH oxidase Nox2, and consequently facilitates reactive-oxygen-species-dependent rupture of phagosomal membrane to allow antigen export to the cytosol. Cybb re-expression in Zeb1-deficient cDC1 fully restores the defective cross-presentation while microRNA-96/182 overexpression in Zeb1-sufficient cDC1 inhibits cross-presentation. Therefore, our results identify a Zeb1-microRNA-96/182-Cybb pathway that controls cross-presentation in cDC1 and uncover an essential role of Zeb1 in cDC1 homeostasis. Type 1 conventional dendritic cells (cDC1) play a pivotal role in the cross-presentation of antigens, enabling efficient CD8 + T cell response. Here authors show that the transcription factor Zeb1 essentially regulates this process via facilitating the reactive-oxygen-species-dependent rupture of phagosomal membrane to allow antigen export to the cytoplasm. [ABSTRACT FROM AUTHOR]

The chicken major histocompatibility complex (MHC, also known as the BF-BL region of the B locus) is notably small and simple with few genes, most of which are involved in antigen processing and presentation. There are two classical class I genes, of which only BF2 is well and systemically expressed as the major ligand for cytotoxic T lymphocytes (CTLs). The other class I gene, BF1, is believed to be primarily a natural killer (NK) cell ligand. Among most standard chicken MHC haplotypes examined in detail, BF1 is expressed tenfold less than BF2 at the RNA level due to defects in the promoter or in a splice site. However, in the B14 and typical B15 haplotypes, BF1 RNA was not detected, and here, we show that a deletion between imperfect 32 nucleotide direct repeats has removed the BF1 gene entirely. The phenotypic effects of not having a BF1 gene (particularly on resistance to infectious pathogens) have not been systematically explored, but such deletions between short direct repeats are also found in some BF1 promoters and in the 5′ untranslated region (5′UTR) of some BG genes found in the BG region of the B locus. Despite the opposite transcriptional orientation of homologous genes in the chicken MHC, which might prevent the loss of key genes from a minimal essential MHC, it appears that small direct repeats can still lead to deletion. [ABSTRACT FROM AUTHOR]

Systemic lupus erythematosus (SLE) is a systemic autoimmune disorder, and numerous aberrations of T cell responses have been reported and were implicated in its pathophysiology. Recently, CD4-positive T cells with cytotoxic potential were shown to be involved in autoimmune disease progression and tissue damage. However, the effector functions of this cell type and their potential molecular mechanisms in SLE patients remain to be elucidated. In this study, we find that cytotoxic CD4+CD28− T cells are expanded in SLE patients with flow cytometry analysis, and the percentage of CD4+CD28− T cells positively correlates with the Systemic Lupus International Collaborating Clinics/ACR Damage Index (SDI). Furthermore, our study suggests that interleukin-15 (IL-15) promotes the expansion, proliferation, and cytotoxic function of CD4+CD28− T cells in SLE patients through activation of the Janus kinase3-STAT5 pathway. Further study indicates that IL-15 not only mediates the upregulation of NKG2D, but also cooperates with the NKG2D pathway to regulate the activation of the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) pathway. Together, our study demonstrated that proinflammatory and cytolytic CD4+CD28− T cells expand in SLE patients. The pathogenic potential of these CD4+CD28− T cells is driven by the coupling of the IL-15/IL-15R signaling pathway and the NKG2D/DAP10 signaling pathway, which may open new avenues for therapeutic intervention to prevent SLE progression. [ABSTRACT FROM AUTHOR]

γδ T cells play a pivotal role in protection against various types of infections and tumours, from early childhood on and throughout life. They consist of several subsets characterised by adaptive and innate-like functions, with Vγ9Vδ2 being the largest subset in human peripheral blood. Although these cells show signs of cytotoxicity, their modus operandi remains poorly understood. Here we explore, using live single-cell imaging, the cytotoxic functions of γδ T cells upon interactions with tumour target cells with high temporal and spatial resolution. While γδ T cell killing is dominated by degranulation, the availability of lytic molecules appears tightly regulated in time and space. In particular, the limited co-occurrence of granzyme B and perforin restrains serial killing of tumour cells by γδ T cells. Thus, our data provide new insights into the cytotoxic arsenal and functions of γδ T cells, which may guide the development of more efficient γδ T cell based adoptive immunotherapies. γδ T cells are unique T lymphocytes with cytotoxic functions, targeting infections and tumours. Here authors show that the target killing function of γδ T cells is tightly regulated at the level of the availability of lytic molecules granzyme B and perforin. [ABSTRACT FROM AUTHOR]

Lytic cell death triggers an antitumour immune response. However, cancer cells evade lytic cell death by several mechanisms. Moreover, a prolonged and uncontrolled immune response conversely leads to T-cell exhaustion. Therefore, an oncolytic system capable of eliciting an immune response by killing cancer cells in a controlled manner is needed. Here, we establish a micro-scale cytotoxic T-cell-inspired oncolytic system (TIOs) to precisely lyse cancer cells by NIR-light-controlled lipid peroxidation. Our TIOs present antigen-based cell recognition, tumour-targeting and catalytic cell-lysis ability; thus, the TIOs induce oncolysis in vivo. We apply TIOs to preclinical cancer models, showing anti-tumor activity with negligible side-effects. Tumour regression is correlated with a T-cell based anti-tumour immune response and TIOs also improve responses to anti-PD-1 therapy or STING activation. Our study provides insights to design oncolytic systems for antitumour immunity. Moreover, activation of STING can reverse T-cell exhaustion in oncolysis. Different types of lytic cell death can trigger an anti-tumor immune response. Here the authors report the design of a near infrared light controllable micron-scale oncolytic system, triggering lipid peroxidation and lytic cell death in tumors as well anti-tumor immunity in preclinical cancer models. [ABSTRACT FROM AUTHOR]

The cGAS-STING signaling pathway has emerged as a promising target for immunotherapy development. Here, we introduce a light-sensitive optogenetic device for control of the cGAS/STING signaling to conditionally modulate innate immunity, called 'light-inducible SMOC-like repeats' (LiSmore). We demonstrate that photo-activated LiSmore boosts dendritic cell (DC) maturation and antigen presentation with high spatiotemporal precision. This non-invasive approach photo-sensitizes cytotoxic T lymphocytes to engage tumor antigens, leading to a sustained antitumor immune response. When combined with an immune checkpoint blocker (ICB), LiSmore improves antitumor efficacy in an immunosuppressive lung cancer model that is otherwise unresponsive to conventional ICB treatment. Additionally, LiSmore exhibits an abscopal effect by effectively suppressing tumor growth in a distal site in a bilateral mouse model of melanoma. Collectively, our findings establish the potential of targeted optogenetic activation of the STING signaling pathway for remote immunomodulation in mice. Optogenetics makes use of light-sensitive proteins to control biological processes using light. Here, the authors present an optogenetic system that regulates the cGAS/STING pathway remotely and demonstrate its efficacy in murine tumour models. [ABSTRACT FROM AUTHOR]

Inhibition of glycolysis in immune cells and cancer cells diminishes their activity, and thus combining immunotherapies with glycolytic inhibitors is challenging. Herein, a strategy is presented where glycolysis is inhibited in cancer cells using PFK15 (inhibitor of PFKFB3, rate-limiting step in glycolysis), while simultaneously glycolysis and function is rescued in DCs by delivery of fructose-1,6-biphosphate (F16BP, one-step downstream of PFKFB3). To demonstrate the feasibility of this strategy, vaccine formulations are generated using calcium-phosphate chemistry, that incorporate F16BP, poly(IC) as adjuvant, and phosphorylated-TRP2 peptide antigen and tested in challenging and established YUMM1.1 tumours in immunocompetent female mice. Furthermore, to test the versatility of this strategy, adoptive DC therapy is developed with formulations that incorporate F16BP, poly(IC) as adjuvant and mRNA derived from B16F10 cells as antigens in established B16F10 tumours in immunocompetent female mice. F16BP vaccine formulations rescue DCs in vitro and in vivo, significantly improve the survival of mice, and generate cytotoxic T cell (Tc) responses by elevating Tc1 and Tc17 cells within the tumour. Overall, these results demonstrate that rescuing glycolysis of DCs using metabolite-based formulations can be utilized to generate immunotherapy even in the presence of glycolytic inhibitor. While glycolysis inhibition impairs cancer cell tumourigenic capacities, it also affects immune cells anti-tumour activity. Here, the authors show that rescuing glycolytic inhibition of dendritic cells improves the efficacy of combining immunotherapy with glycolysis inhibition. [ABSTRACT FROM AUTHOR]

Response to immunotherapy widely varies among cancer patients and identification of parameters associating with favourable outcome is of great interest. Here we show longitudinal monitoring of peripheral blood samples of non-small cell lung cancer (NSCLC) patients undergoing anti-PD1 therapy by high-dimensional cytometry by time of flight (CyTOF) and Meso Scale Discovery (MSD) multi-cytokines measurements. We find that higher proportions of circulating CD8+ and of CD8+CD101hiTIM3+ (CCT T) subsets significantly correlate with poor clinical response to immune therapy. Consistently, CD8+ T cells and CCT T cell frequencies remain low in most responders during the entire multi-cycle treatment regimen; and higher killer cell lectin-like receptor subfamily G, member 1 (KLRG1) expression in CCT T cells at baseline associates with prolonged progression free survival. Upon in vitro stimulation, CCT T cells of responders produce significantly higher levels of cytokines, including IL-1β, IL-2, IL-8, IL-22 and MCP-1, than of non-responders. Overall, our results provide insights into the longitudinal immunological landscape underpinning favourable response to immune checkpoint blockade therapy in lung cancer patients. Immune checkpoint blockade therapy improved the survival rates of non-small cell lung cancer but only a proportion of patients benefit. Here authors follow the humoral and cellular immunological parameters of patients undergoing anti-PD1 therapy longitudinally and find that levels and functional properties of cytotoxic T cells, and especially CD8+CD101hiTIM3+ cells determine the response. [ABSTRACT FROM AUTHOR]

Pronounced immune escape by the SARS-CoV-2 Omicron variant has resulted in many individuals possessing hybrid immunity, generated through a combination of vaccination and infection. Concerns have been raised that omicron breakthrough infections in triple-vaccinated individuals result in poor induction of omicron-specific immunity, and that prior SARS-CoV-2 infection is associated with immune dampening. Taking a broad and comprehensive approach, we characterize mucosal and blood immunity to spike and non-spike antigens following BA.1/BA.2 infections in triple mRNA-vaccinated individuals, with and without prior SARS-CoV-2 infection. We find that most individuals increase BA.1/BA.2/BA.5-specific neutralizing antibodies following infection, but confirm that the magnitude of increase and post-omicron titres are higher in the infection-naive. In contrast, significant increases in nasal responses, including neutralizing activity against BA.5 spike, are seen regardless of infection history. Spike-specific T cells increase only in infection-naive vaccinees; however, post-omicron T cell responses are significantly higher in the previously-infected, who display a maximally induced response with a highly cytotoxic CD8+ phenotype following their 3rd mRNA vaccine dose. Responses to non-spike antigens increase significantly regardless of prior infection status. These findings suggest that hybrid immunity induced by omicron breakthrough infections is characterized by significant immune enhancement that can help protect against future omicron variants. The authors characterize immune response in Omicron-infected vaccinated individuals and observe an immune enhancement. While increases in neutralizing antibodies and spike T cells are stronger in previously naïve individuals, mucosal antibodies and non-spike responses increase regardless of infection history. [ABSTRACT FROM AUTHOR]

Dendritic cell (DC) vaccine was among the first FDA-approved cancer immunotherapies, but has been limited by the modest cytotoxic T lymphocyte (CTL) response and therapeutic efficacy. Here we report a facile metabolic labeling approach that enables targeted modulation of adoptively transferred DCs for developing enhanced DC vaccines. We show that metabolic glycan labeling can reduce the membrane mobility of DCs, which activates DCs and improves the antigen presentation and subsequent T cell priming property of DCs. Metabolic glycan labeling itself can enhance the antitumor efficacy of DC vaccines. In addition, the cell-surface chemical tags (e.g., azido groups) introduced via metabolic glycan labeling also enable in vivo conjugation of cytokines onto adoptively transferred DCs, which further enhances CTL response and antitumor efficacy. Our DC labeling and targeting technology provides a strategy to improve the therapeutic efficacy of DC vaccines, with minimal interference upon the clinical manufacturing process. Dendritic cell (DC) vaccines were among the first FDA-approved cancer immunotherapies but have been limited by the modest therapeutic efficacy. Here, authors report a facile metabolic glycan labeling approach to improving the cytotoxic T lymphocyte response and antitumor efficacy of DC vaccines. [ABSTRACT FROM AUTHOR]

Lack of sufficient cytotoxic T lymphocytes (CD8+ T cells) infiltration and dysfunctional state of CD8+ T cells are considered enormous obstacles to antitumor immunity. Herein, we construct a synergistic nanoplatform to promote CD8+ T cell infiltration in tumors while restoring T cell function by regulating methionine metabolism and activating the STING innate immune pathway. The CRISPR/Cas9 system down-regulates the methionine transporter SLC43A2 and restricts the methionine uptake by tumor cells, thereby relieving the methionine competition pressure of T cells; simultaneously, the released nutrition metal ions activate the cGAS/STING pathway. In this work, the described nanoplatform can enhance the effect of immunotherapy in preclinical cancer models in female mice, enhancing STING pathway mediated immunity and facilitating the development of amino acid metabolic intervention-based cancer therapy. Metabolic pressure, in particular the lack of methionine availability, on tumor-infiltrating CD8 + T cells is associated with T cell dysfunction. Since tumor cells rely on SLC43A2 for methionine uptake, here the authors design a nanoplatform for CRISPR/Cas9 mediated silencing of SLC43A2 and STING activation, restoring anti-tumor T cell immune responses. [ABSTRACT FROM AUTHOR]