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Background: Tumor immunotherapy can not only eliminate the primary lesion, but also produce long-term immune memory, effectively inhibiting tumor metastasis and recurrence. However, immunotherapy also showed plenty of limitations in clinical practice. In recent years, the combination of nanomaterials and immunotherapy has brought new light for completely eliminating tumors with its fabulous anti-tumor effects and negligible side effects. Methods: The Core Collection of Web of Science (WOSCC) was used to retrieve and obtain relevant literatures on antitumor nano-immunotherapy since the establishment of the WOSCC. Bibliometrix, VOSviewer, CiteSpace, GraphPad Prism, and Excel were adopted to perform statistical analysis and visualization. The annual output, active institutions, core journals, main authors, keywords, major countries, key documents, and impact factor of the included journals were evaluated. Results: A total of 443 related studies were enrolled from 2004 to 2022, and the annual growth rate of articles reached an astonishing 16.85%. The leading countries in terms of number of publications were China and the United States. Journal of Controlled Release, Biomaterials, Acta Biomaterialia, Theranostics, Advanced Materials, and ACS Nano were core journals publishing high-quality literature on the latest advances in the field. Articles focused on dendritic cells and drug delivery accounted for a large percentage in this field. Key words such as regulatory T cells, tumor microenvironment, immune checkpoint blockade, drug delivery, photodynamic therapy, photothermal therapy, tumor-associated macrophages were among the hottest themes with high maturity. Dendritic cells, vaccine, and T cells tend to become the popular and emerging research topics in the future. Conclusions: The combined treatment of nanomaterials and antitumor immunotherapy, namely antitumor nano-immunotherapy has been paid increasing attention. Antitumor nano-immunotherapy is undergoing a transition from simple to complex, from phenotype to mechanism. [ABSTRACT FROM AUTHOR]

Abdominal aortic aneurysm (AAA) is characterized by inflammatory cell infiltration, extracellular matrix (ECM) degradation, and vascular smooth muscle cell (SMC) dysfunction. The inflammatory cells involved in AAA mainly include immune cells including macrophages, neutrophils, T-lymphocytes and B lymphocytes and endothelial cells. As the blood vessel wall expands, more and more lymphocytes infiltrate into the outer membrane. It was found that more than 50% of lymphocytes in AAA tissues were CD3+ T cells, including CD4+, CD8+T cells, gd T cells and regulatory T cells (Tregs). Due to the important role of T cells in inflammatory response, an increasing number of researchers have paid attention to the role of T cells in AAA and dug into the relevant mechanism. Therefore, this paper focuses on reviewing the immunoregulatory role of T cells in AAA and their role in immunotherapy, seeking potential targets for immunotherapy and putting forward future research directions. [ABSTRACT FROM AUTHOR]

Esophageal cancer is a prevalent tumor of the digestive tract worldwide. The detection rate of early-stage esophageal cancer is very low, and most patients are diagnosed with metastasis. Metastasis of esophageal cancer mainly includes direct diffusion metastasis, hematogenous metastasis, and lymphatic metastasis. This article reviews the metabolic process of esophageal cancer metastasis and the mechanisms by which M2 macrophages, CAF, regulatory T cells, and their released cytokines, including chemokines, interleukins, and growth factors, form an immune barrier to the anti-tumor immune response mediated by CD8+ T cells, impeding their ability to kill tumor cells during tumor immune escape. The effect of Ferroptosis on the metastasis of esophageal cancer is briefly mentioned. Moreover, the paper also summarizes common drugs and research directions in chemotherapy, immunotherapy, and targeted therapy for advanced metastatic esophageal cancer. This review aims to serve as a foundation for further investigations into the mechanism and management of esophageal cancer metastasis. [ABSTRACT FROM AUTHOR]

Background: Clinical studies have shown that the efficacy of programmed cell death receptor-1/programmed cell death ligand-1 (PD-1/PD-L1) inhibitors on glioblastoma (GBM) is much lower than what is expected because of the low immunogenicity of GBM. Ferroptosis of cancer cells can induce the maturation of dendritic cells (DC cells) and increase the activity of T cell. The activated T cells release IFN-γ, which subsequently induces the ferroptosis of cancer cells. Thus, the aim of this paper is to set up a new GBM-targeted drug delivery system (Fe3O4-siPD-L1@M-BV2) to boost ferroptosis for immunotherapy of drug-resistant GBM. Results: Fe3O4-siPD-L1@M-BV2 significantly increased the accumulation of siPD-L1 and Fe2+ in orthotopic drug-resistant GBM tissue in mice. Fe3O4-siPD-L1@M-BV2 markedly decreased the protein expression of PD-L1 and increased the ratio between effector T cells and regulatory T cells in orthotopic drug-resistant GBM tissue. Moreover, Fe3O4-siPD-L1@M-BV2 induced ferroptosis of GBM cells and maturation of DC cell, and it also increased the ratio between M1-type microglia and M2-type microglia in orthotopic drug-resistant GBM tissue. Finally, the growth of orthotopic drug-resistant GBM in mice was significantly inhibited by Fe3O4-siPD-L1@M-BV2. Conclusion: The mutual cascade amplification effect between ferroptosis and immune reactivation induced by Fe3O4-siPD-L1@M-BV2 significantly inhibited the growth of orthotopic drug-resistant GBM and prolonged the survival time of orthotopic drug-resistant GBM mice. [ABSTRACT FROM AUTHOR]

• FOXP3 controls Treg differentiation and activity. • FOXP3 induces metabolic versatility in intra-tumoral Tregs. • Treg subsets show different reliance on FOXP3. Dysregulation of regulatory T cells (Tregs) is described in the context of inflammatory and autoimmune diseases, and cancer. Forkhead box P3 (FOXP3) is a transcription factor that its activity is an indicator of Treg identity. FOXP3 induces metabolic versatility in intra-tumoral Tregs, so that its deficiency mediates Treg instability or even gives rise to the acquisition of effector T cell phenotype. FOXP3 dysregulation and defectiveness occurs upon ubiquitination, methylation and presumably acetylation. Stimulators of PTEN, mammalian target of rapamycin complex 2 (mTORC2), and nucleus accumbens–associated protein-1 (NAC1), and inhibitors of B lymphocyte-induced maturation protein-1 (Blimp-1), Deltex1 (DTX1) and ubiquitin-specific peptidase 22 (USP22) are suggested to hamper FOXP3 stability, and to promote its downregulation and further Treg depletion. A point is that Treg subsets reveal different reliance on FOXP3, which indicates that not all Tregs are strictly dependent on FOXP3, and presumably Tregs with different origin rely on diverse regulators of FOXP3 stability. The focus of this review is over the current understanding toward FOXP3, its activity in Tregs and influence from different regulators within tumor microenvironment (TME). Implication of FOXP3 targeting in cancer immunotherapy is another focus of this paper. [ABSTRACT FROM AUTHOR]

Background: Polymerized allergoids conjugated with mannan represent a novel approach of allergen immunotherapy targeting dendritic cells. In this study, we aimed to determine the optimal dose of mannan-allergoid conjugates derived from grass pollen (Phleum pratense and Dactylis glomerata) administered via either the subcutaneous or sublingual route. Methods: A randomized, double-blind, placebo-controlled trial with a doubledummy design was conducted, involving 162 participants across 12 centers in Spain. Subjects were randomly allocated to one of nine different treatment groups, each receiving either placebo or active treatment at doses of 500, 1,000, 3,000, or 5,000 mTU/mL over four months. Each participant received five subcutaneous (SC) doses of 0.5 mL each, every 30 days, and a daily sublingual (SL) dose of 0.2 mL. Participants who received active treatment through SC, received placebo through SL. Participants who received active treatment through SL, received placebo SC. One Group, as control, received bot SC and SL placebo. The primary efficacy outcome was the improvement in titrated nasal provocation tests (NPT) at the end of the study compared to baseline. Secondary outcomes included specific antibody (IgG4, IgE) and cellular (IL-10 producing and regulatory T cell) responses. All adverse events and side reactions were recorded and assessed. Results: Post-treatment, the active groups showed improvements in NPT ranging from 33% to 53%, with the highest doses showing the greatest improvements regardless of the administration route. In comparison, the placebo group showed a 12% improvement. Significant differences over placebo were observed at doses of 3,000 mTU/mL (p=0.049 for SL, p=0.015 for SC) and 5,000 mTU/mL (p=0.011 for SL, p=0.015 for SC). A dose-dependent increase in IgG4 was observed following SC administration, and an increase in IL-10 producing cells for both routes of administration. No serious systemic or local adverse reactions were recorded, and no adrenaline was required. Conclusion: Grass pollen immunotherapy with mannan-allergoid conjugates was found to be safe and efficacious in achieving the primary outcome, whether administered via the subcutaneous or sublingual routes, at doses of 3,000 and 5,000 mTU/mL. [ABSTRACT FROM AUTHOR]

Considerable attention has been directed towards exploring the potential efficacy of miR-155 in the realm of cancer immunotherapy. Elevated levels of miR-155 in dendritic cells (DCs) have been shown to enhance their maturation, migration, cytokine secretion, and their ability to promote T cell activation. In addition, overexpression of mir155 in M2 macrophages boost the polarization towards the M1 phenotype. Conversely, miR-155 has the propensity to induce the accumulation of immunosuppressive cells like regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs) in the tumor tissue. To account for this discrepancy, it is imperative to get help from a drug that could deal with immunosuppressive effect. Curcumin (CUR) exhibits the capacity to prompt Tregs converse into T helper 1 cells, fostering the polarization of M2 tumor-associated macrophage towards the M1 phenotype, and impeding the recruitment and aggregation of MDSCs within the tumor microenvironment. Nonetheless, CUR is known to exert an immunosuppressive impact on DCs by hindering the expression of maturation markers, cytokines, and chemokines, thereby prevent DCs response to immunostimulatory agents. Hence, a reactive oxygen species/glutathione dual responsive drug conveyance platform (CUR/miR155@DssD-Hb NPs) was devised to co-deliver CUR and miR155, with the aim of exploring their synergistic potential in bolstering a sustained and robust anti-tumor immune response. In vitro and in vivo results have suggested that CUR/miR155@DssD-Hb NPs can effectively inhibit the viability of 4T1 and B16F10 tumor cells, trigger the release of damage associated molecular patterns, stimulate DCs maturation, subsequent activation of CD8+ T cells, diminish immunosuppressive cell populations (MDSCs, Tregs, M2 TAMs and exhausted T cells), promote the formation of long-term immunity and lessen the formation of metastatic nodules in the lungs. In summary, the co-delivery system integrating CUR and miR155 (CUR/miR155@DssD-Hb NPs) demonstrates promise as a promising strategy for the immunotherapy of melanoma and triple negative breast cancer. [ABSTRACT FROM AUTHOR]

This article provides an overview of recent advancements in veterinary cancer immunology, focusing on how the immune system interacts with animal cancer cells. It discusses novel immunotherapeutic approaches, such as cancer vaccines and monoclonal antibodies, that have shown promise in treating canine cancers. Comparative oncology, which examines cancer across different species, is highlighted as a valuable approach for identifying common mechanisms and potential treatments. The article also mentions the potential of chimeric antigen receptors (CARs) in veterinary immuno-oncology, although their use in veterinary medicine is still under development. The document is a collection of research articles covering various topics related to cancer treatment in animals, providing new insights and potential therapeutic strategies for veterinary oncology. Ongoing research in this field is crucial for improving cancer management and treatment options for dogs. [Extracted from the article]

Over the past two decades, immunotherapies have increasingly been considered as first-line treatments for most cancers. One such treatment is immune checkpoint blockade (ICB), which has demonstrated promising results against various solid tumors in clinical trials. Monoclonal antibodies (mAbs) are currently available as immune checkpoint inhibitors (ICIs). These ICIs target specific immune checkpoints, including cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) and programmed cell death protein 1 (PD-1). Clinical trial results strongly support the feasibility of this immunotherapeutic approach. However, a substantial proportion of patients with cancer develop resistance or tolerance to treatment, owing to tumor immune evasion mechanisms that counteract the host immune response. Consequently, substantial research focus has been aimed at identifying additional ICIs or synergistic inhibitory receptors to enhance the effectiveness of anti-PD-1, anti-programmed cell death ligand 1 (anti-PD-L1), and anti-CTLA-4 treatments. Recently, several immune checkpoint molecular targets have been identified, such as T cell immunoreceptor with Ig and ITIM domains (TIGIT), mucin domain containing-3 (TIM-3), lymphocyte activation gene-3 (LAG-3), V-domain immunoglobulin suppressor of T cell activation (VISTA), B and T lymphocyte attenuator (BTLA), and signal-regulatory protein a (SIRPa). Functional mAbs targeting these molecules are under development. CTLA-4, PD-1/PD-L1, and other recently discovered immune checkpoint proteins with distinct structures are at the forefront of research. This review discusses these structures, as well as clinical progress in mAbs targeting these immune checkpoint molecules and their potential applications. [ABSTRACT FROM AUTHOR]

Bladder cancer is a heterogenous disease, and molecular subtyping is a promising method to capture this variability. Currently, the immune compartment in relation to subtypes is poorly characterized. Here, we analyzed the immune compartment in bladder tumors and normal bladder urothelium with a focus on T cell subpopulations using flow cytometry and RNA sequencing. The results were investigated in relation to tumor invasiveness (NMIBC/MIBC) and molecular subtypes according to the Lund Taxonomy system. Whereas the NMIBC/MIBC differed in the overall immune infiltration only, the molecular subtypes differed both in terms of immune infiltration and immune compartment compositions. The Basal/Squamous (Ba/Sq) and genomically unstable (GU) tumors displayed increased immune infiltration compared to urothelial-like (Uro) tumors. Additionally, the GU tumors had a higher proportion of regulatory T cells within the immune compartment compared to Uro tumors. Furthermore, sequencing showed higher levels of exhaustion in CD8+ T cells from GU tumors compared to both Uro tumors and the control. Although no such difference was detected at the transcriptomic level in Uro tumors compared to the controls, CD8+ T cells in Uro tumors showed higher expression of several exhaustion markers at the protein level. Taken together, our findings indicate that depending on the molecular subtype, different immunotherapeutic interventions might be warranted. [ABSTRACT FROM AUTHOR]

The IFN-type-I pathway is involved in radiotherapy (RT)-mediated immune responses. Large RT fractions have been suggested to potently induce this pathway. Neoadjuvant hypofractionated short-course (scRT) and conventional long-course (lcRT) RT applied for the treatment of locally advanced rectal adenocarcinoma patients provides a unique model to address the immuno-stimulatory properties of RT on a systemic level. We prospectively analyzed the IFNβ plasma levels and lymphocyte counts (LCs) of rectal adenocarcinoma patients before and after treatment with scRT (n = 22) and lcRT (n = 40). Flow cytometry was conducted to assess the effects on lymphocytic subpopulations in a subset of 20 patients. A statistically significant increase in the post-RT IFNβ plasma levels was noted in patients undergoing scRT (p = 0.004). Improved pathological tumor regression was associated with elevated post-RT IFNβ levels (p = 0.003). Although all patients experienced substantial lymphopenia after treatment, the post-RT LC of patients treated with scRT were significantly higher compared to lcRT (p = 0.001). Patients undergoing scRT displayed significantly lower percentages of regulatory CD4+/CD25+ T-cells after therapy (p = 0.02). scRT enables effective stimulation of the IFN-type-I pathway on a systemic level and confers decreased lymphocytic cytotoxicity and limited regulatory T-cell activation compared to lcRT, supporting its increasing role in immuno-RT trials. [ABSTRACT FROM AUTHOR]

Background: Accurate microsatellite instability (MSI) testing is essential for identifying gastric cancer (GC) patients eligible for immunotherapy. We aimed to develop and validate a CT-based radiomics signature to predict MSI and immunotherapy outcomes in GC. Methods: This retrospective multicohort study included a total of 457 GC patients from two independent medical centers in China and The Cancer Imaging Archive (TCIA) databases. The primary cohort (n = 201, center 1, 2017–2022), was used for signature development via Least Absolute Shrinkage and Selection Operator (LASSO) and logistic regression analysis. Two independent immunotherapy cohorts, one from center 1 (n = 184, 2018–2021) and another from center 2 (n = 43, 2020–2021), were utilized to assess the signature's association with immunotherapy response and survival. Diagnostic efficiency was evaluated using the area under the receiver operating characteristic curve (AUC), and survival outcomes were analyzed via the Kaplan-Meier method. The TCIA cohort (n = 29) was included to evaluate the immune infiltration landscape of the radiomics signature subgroups using both CT images and mRNA sequencing data. Results: Nine radiomics features were identified for signature development, exhibiting excellent discriminative performance in both the training (AUC: 0.851, 95%CI: 0.782, 0.919) and validation cohorts (AUC: 0.816, 95%CI: 0.706, 0.926). The radscore, calculated using the signature, demonstrated strong predictive abilities for objective response in immunotherapy cohorts (AUC: 0.734, 95%CI: 0.662, 0.806; AUC: 0.724, 95%CI: 0.572, 0.877). Additionally, the radscore showed a significant association with PFS and OS, with GC patients with a low radscore experiencing a significant survival benefit from immunotherapy. Immune infiltration analysis revealed significantly higher levels of CD8 + T cells, activated CD4 + B cells, and TNFRSF18 expression in the low radscore group, while the high radscore group exhibited higher levels of T cells regulatory and HHLA2 expression. Conclusion: This study developed a robust radiomics signature with the potential to serve as a non-invasive biomarker for GC's MSI status and immunotherapy response, demonstrating notable links to post-immunotherapy PFS and OS. Additionally, distinct immune profiles were observed between low and high radscore groups, highlighting their potential clinical implications. [ABSTRACT FROM AUTHOR]

This article explores the potential of peptide drugs in cancer immunotherapy. Peptides offer advantages such as selectivity, infiltration into solid tumors, and easy synthesis, making them promising candidates for immune checkpoint inhibition. The article discusses the development of peptide inhibitors that target immune checkpoints like PD-1/PD-L1, TIGIT/PVR, and CD47/SIRPα. It also explores the use of dual-function peptides that can target multiple signaling pathways simultaneously. Additionally, the article mentions the conjugation of peptides with small molecule drugs to create peptide-drug conjugates and self-assembly nanoparticles for enhanced therapeutic effects. The article emphasizes the need for further research in oral peptide delivery and the combination of immune checkpoint blockade with peptide vaccines for a synergistic anti-tumor response. [Extracted from the article]

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer‐related death worldwide. Hepatectomy remains the first‐line treatment for patients with resectable HCC. However, the reported recurrence rate of HCC at 5 years after surgery is between 50% and 70%. Tumor‐related factors, including tumor size, number and differentiation, and underlying liver disease are well‐known risk factors for recurrence after treatment. In addition to tumor‐related factors, ever‐increasing amounts of studies are finding that the tumor microenvironment also plays an important role in the recurrence of HCC, including systemic inflammatory response and immune regulation. Based on this, some inflammatory and immune markers were used in predicting postoperative cancer recurrence. These include neutrophil‐to‐lymphocyte ratio, platelet‐to‐lymphocyte ratio, cytotoxic T cells, and regulatory T cells, among others. In this review, we summarized the inflammatory and immune markers that affect recurrence after HCC resection in order to provide direction for adjuvant therapy after HCC resection and ultimately achieve the goal of reducing recurrence. [ABSTRACT FROM AUTHOR]

Background: Immune checkpoint inhibitors, which have attracted much attention in recent years, have achieved good efficacy, but their use is limited by the high incidence of acquired drug resistance. Therefore, there is an urgent need to develop new immunotherapy drugs. Compound taxus chinensis capsule (CTC) is an oral paclitaxel compound drug, clinical results showed it can change the number of regulatory T cells and T helper cell 17 in peripheral blood. Regulating the balance between regulatory T cells and T helper cell 17 is considered to be an effective anticancer strategy. Paclitaxel and ginsenoside metabolite compound K are the main immunomodulatory components, it is not clear that paclitaxel combined with compound K can inhibit tumor development by regulating the balance between regulatory T cell and T helper cell 17. Methods: MTT, EdU proliferation and plate colony formation assay were used to determine the concentration of paclitaxel and compound K. AnnexinV-FITC/PI staining, ELISA, Western Blot assay, Flow Cytometry and Immunofluorescence were used to investigate the effect of paclitaxel combined with compound K on Lewis cell cultured alone or co-cultured with splenic lymphocyte. Finally, transplanted tumor C57BL/6 mice model was constructed to investigate the anti-cancer effect in vivo. Results: According to the results of MTT, EdU proliferation and plate colony formation assay, paclitaxel (10 nM) and compound K (60 μM) was used to explore the mechanism. The results of Flow Cytometry demonstrated that paclitaxel combined with compound K increased the number of T helper cell 17 and decreased the number of regulatory T cells, which induced pyroptosis of cancer cells. The balance was mediated by the JAK–STAT pathway according to the results of Western Blot and Immunofluorescence. Finally, the in vivo results showed that paclitaxel combined with compound K significantly inhibit the progression of lung cancer. Conclusions: In this study, we found that paclitaxel combined with compound K can activate CD8+ T cells and induce pyroptosis of tumor cells by regulating the balance between regulatory T cells and T helper cell 17. These results demonstrated that this is a feasible treatment strategy for lung cancer. [ABSTRACT FROM AUTHOR]

A recent study published in the journal MedComm discusses a novel tumor immunotherapy strategy that targets protein tyrosine phosphatases nonreceptor type 2 (PTPN2) and nonreceptor type 1 (PTPN1) using a small molecule inhibitor called AC484. The researchers designed AC484 based on the protein structure of PTPN2 and PTPN1 and found that it enhances antitumor immunity through various mechanisms, such as increasing tumor sensitivity to IFN-γ, improving T-cell functions, stimulating tumor microenvironment inflammation, expanding TCR diversity, and preventing T-cell exhaustion. AC484 has shown promising results in preclinical studies and is currently being evaluated in Phase I clinical trials for the treatment of solid tumors. The study provides important insights for the development of innovative cancer drugs and future research in tumor immunotherapy. [Extracted from the article]

Background: Regulatory T cells (Tregs) maintain immune tolerance. While Treg-mediated neuroprotective activities are now well-accepted, the lack of defined antigen specificity limits their therapeutic potential. This is notable for neurodegenerative diseases where cell access to injured brain regions is required for disease-specific therapeutic targeting and improved outcomes. To address this need, amyloid-beta (Aβ) antigen specificity was conferred to Treg responses by engineering the T cell receptor (TCR) specific for Aβ (TCRAβ). The TCRAb were developed from disease-specific T cell effector (Teff) clones. The ability of Tregs expressing a transgenic TCRAβ (TCRAβ -Tregs) to reduce Aβ burden, transform effector to regulatory cells, and reverse disease-associated neurotoxicity proved beneficial in an animal model of Alzheimer's disease. Methods: TCRAβ -Tregs were generated by CRISPR-Cas9 knockout of endogenous TCR and consequent incorporation of the transgenic TCRAb identified from Aβ reactive Teff monoclones. Antigen specificity was confirmed by MHC-Aβ-tetramer staining. Adoptive transfer of TCRAβ-Tregs to mice expressing a chimeric mouse-human amyloid precursor protein and a mutant human presenilin-1 followed measured behavior, immune, and immunohistochemical outcomes. Results: TCRAβ-Tregs expressed an Aβ-specific TCR. Adoptive transfer of TCRAβ-Tregs led to sustained immune suppression, reduced microglial reaction, and amyloid loads. 18F-fluorodeoxyglucose radiolabeled TCRAβ-Treg homed to the brain facilitating antigen specificity. Reduction in amyloid load was associated with improved cognitive functions. Conclusions: TCRAβ-Tregs reduced amyloid burden, restored brain homeostasis, and improved learning and memory, supporting the increased therapeutic benefit of antigen specific Treg immunotherapy for AD. [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]

Introduction: Regulatory T cell (Treg)-targeting cancer immunotherapy aims to transiently deplete Treg cells in the tumor microenvironment, without affecting effector T cells (Teff), thus both enhancing anti-tumor activity and avoiding autoimmunity. This study evaluated whether adding E7777 (a new formulation of denileukin diftitox [DD]) improved the efficacy of anti-PD-1 antibody therapy. DD is a recombinant protein containing the hydrophobic and catalytic portions of diphtheria toxin fused to full-length human IL-2. E7777 has the same amino acid sequence and brief circulatory half-life as DD, but with greater purity and potency. Methods: Subcutaneous syngeneic murine solid tumor models (colon cancer CT-26 and liver cancer H22) were used to evaluate safety, efficacy, and overall survival with E7777 and anti-PD-1 antibodies, each administered as monotherapy or in concurrent or sequential combination. In Experiment 1, treatments were compared to assess anti-tumor activity at various time points, with tumors excised and dissociated and tumor leukocytes characterized. In Experiment 2, tumor growth, response, and overall survival were characterized for 100 days following a 3-week treatment. Results: E7777 administered in combination with anti-PD-1 led to significantly increased anti-tumor activity and durable, extended overall survival compared to either treatment alone. In both tumor models, the Treg cell infiltration induced by anti-PD-1 treatment was counterbalanced by co-treatment with E7777, suggesting potential synergistic activity. Combination therapy showed the most favorable results. Treatment with E7777 was safe and well-tolerated. Discussion: Combined E7777 and anti-PD-1 therapy was well tolerated and more effective than monotherapy with either drug. [ABSTRACT FROM AUTHOR]

V-domain immunoglobulin suppressor of T cell activation (VISTA) is a novel negative checkpoint receptor (NCR) primarily involved in maintaining immune tolerance. It has a role in the pathogenesis of autoimmune disorders and cancer and has shown promising results as a therapeutic target. However, there is still some ambiguity regarding the ligands of VISTA and their interactions with each other. While V-Set and Immunoglobulin domain containing 3 (VSIG-3) and P-selectin glycoprotein ligand-1(PSGL-1) have been extensively studied as ligands for VISTA, the others have received less attention. It seems that investigating VISTA ligands, reviewing their functions and roles, as well as outcomes related to their interactions, may allow an understanding of their full functionality and effects within the cell or the microenvironment. It could also help discover alternative approaches to target the VISTA pathway without causing related side effects. In this regard, we summarize current evidence about VISTA, its related ligands, their interactions and effects, as well as their preclinical and clinical targeting agents. [ABSTRACT FROM AUTHOR]

Background: Epstein–Barr virus (EBV)‐associated gastric lymphoepithelioma‐like carcinoma (EBVaGLELC) represents a small number of gastric cancer (GC), and research on tumor microenvironment (TME) and treatment strategy are still lacking. Aims: Here, we aim to elucidate the immune features of this rare disease and further help to develop more effective treatment options. Materials & Methods: A retrospective analysis was conducted between 2019 to 2022 in West China Hospital to reveal the immunological characteristics of EBV‐positive GLELC. The difference of immune cell subset and tumor vascular structure between gastric denocarcinoma (GAC) and EBVaGLELC will be pointed out. Discussion: 13 patients with GELEC and 8 patients with GAC were retrospectively studied. The heterogeneity of the immune cell profile was then confirmed through multiplexed immunofluorescence staining (mIF), which revealed a higher proportion of CD3+ T cells, CD8+ T cells, and Treg cells in the EBV‐associated GLELC group. Such a distinct TME may provide therapeutic advantages, and patients with this rare subtype of GC could be good candidates for immune checkpoint inhibitors (ICIs). Angiogenesis in EBV‐positive GLELC may be less intense than that in gastric adenocarcinoma (GAC), a feature that might decrease their susceptibility to antiangiogenic therapy. Furthermore, we reported a 52‐year‐old male with advanced EBV‐positive GLELC who showed a favorable response to the combined therapy with. A repeat evaluation showed sustained partial response (PR), and the progression‐free survival (PFS) was more than 34 months until now. Conclusion: Compared with GAC, EBVaGLELC revealed higher T cell infiltration and less intense of angiogenesis. It displays relatively "hot" TME that may provide the rationality to treat with immunotherapy in EBV‐related GLELC. [ABSTRACT FROM AUTHOR]

Regulatory T cells (Treg), as members of CD4+ T cells, have garnered extensive attention in the research of tumor progression. Treg cells have the function of inhibiting the immune effector cells, preventing tissue damage, and suppressing inflammation. Under the stimulat ion of the tumor inflammatory microenvironment (IM), the reprogramming of Treg cells enhances their suppression of immune responses, ultimately promoting tumor immune escape or tumor progression. Reducing the number of Treg cells in the IM or lowering the activity of Treg cells while preventing their reprogramming, can help promote the body's anti-tumor immune responses. This review introduces a reprogramming mechanism of Treg cells in the IM; and discusses the regulation of Treg cells on tumor progression. The control of Treg cells and the response to Treg inflammatory reprogramming in tumor immunotherapy are analyzed and countermeasures are proposed. This work will provide a foundation for downregulating the immunosuppressive role of Treg in the inflammatory environment in future tumor immunotherapy. [ABSTRACT FROM AUTHOR]

Costimulatory receptors on immune cells represent attractive targets for immunotherapy given that these molecules can increase the frequency of individual protective immune cell populations and their longevity, as well as enhance various effector functions. 4-1BB, a member of the TNF receptor superfamily, also known as CD137 and TNFRSF9, is one such molecule that is inducible on several cell types, including T cells and NK cells. Preclinical studies in animal models have validated the notion that stimulating 4-1BB with agonist reagents or its natural ligand could be useful to augment conventional T cell and NK cell immunity to protect against tumor growth and against viral infection. Additionally, stimulating 4-1BB can enhance regulatory T cell function and might be useful in the right context for suppressing autoimmunity. Two human agonist antibodies to 4-1BB have been produced and tested in clinical trials for cancer, with variable results, leading to the production of a wealth of second-generation antibody constructs, including bi- and multi-specifics, with the hope of optimizing activity and selectivity. Here, we review the progress to date in agonism of 4-1BB, discuss the complications in targeting the immune system appropriately to elicit the desired activity, together with challenges in engineering agonists, and highlight the untapped potential of manipulating this molecule in infectious disease and autoimmunity. [ABSTRACT FROM AUTHOR]

Anti-CTLA-4 antibodies have successfully elicited durable tumor regression in the clinic; however, long-term benefit is limited to a subset of patients for select cancer indications. The incomplete understanding of their mechanism of action has hindered efforts at improvement, with conflicting hypotheses proposing either antagonism of the CTLA-4: B7 axis or Fc effector-mediated regulatory T cell (Treg) depletion governing efficacy. Here, we report the engineering of a nonantagonistic CTLA-4 binding domain (b1s1e2) that depletes intratumoral Tregs as an Fc fusion. Comparison of b1s1e2-Fc to 9d9, an antagonistic anti-CTLA-4 antibody, allowed for interrogation of the separate contributions of CTLA-4 antagonism and Treg depletion to efficacy. Despite equivalent levels of intratumoral Treg depletion, 9d9 achieved more long-term cures than b1s1e2-Fc in MC38 tumors, demonstrating that CTLA-4 antagonism provided additional survival benefit. Consistent with prior reports that CTLA-4 antagonism enhances priming, treatment with 9d9, but not b1s1e2-Fc, increased the percentage of activated T cells in the tumor-draining lymph node (tdLN). Treg depletion with either construct was restricted to the tumor due to insufficient surface CTLA-4 expression on Tregs in other compartments. Through intratumoral administration of diphtheria toxin in Foxp3-DTR mice, we show that depletion of both intratumoral and nodal Tregs provided even greater survival benefit than 9d9, consistent with Treg-driven restraint of priming in the tdLN. Our data demonstrate that anti-CTLA-4 therapies require both CTLA-4 antagonism and intratumoral Treg depletion for maximum efficacy--but that potential future therapies also capable of depleting nodal Tregs could show efficacy in the absence of CTLA-4 antagonism. [ABSTRACT FROM AUTHOR]

Atopic dermatitis (AD) is a chronically relapsing inflammatory skin disorder characterized by itching and eczematous lesions. It is often associated with a personal or familial history of allergic diseases. Allergic inflammation induced by immunoglobulin E and T-helper type 2 (Th2) cell responses to common environmental agents has been suggested to play an essential role in AD pathogenesis. The standard therapies for AD, including topical or systemic agents, focus on controlling skin inflammation. Recently developed monoclonal antibody to interleukin-4 receptor alpha or Janus kinase inhibitors can provide significant clinical improvements in patients with AD by inhibiting Th2 cell-mediated skin inflammation. However, the clinical efficacy of the Th2 cell-targeted therapy is transient and incomplete in patients with AD. Patients with AD are seeking a permanent cure. Therefore, the development of novel immunomodulatory strategies that can improve a long-term clinical outcome and provide a long-term treatment-free clinical remission of AD (disease-modifying therapy) is needed. Regulatory T (Treg) cells play a critical role in the maintenance of immune tolerance and suppress the development of autoimmune and allergic diseases. This review provides three working hypotheses and perspectives for the treatment of AD by Treg cell activation. (1) A decreased number or function of Treg cells is a critical event that causes the activation of Th2 cells, leading to the development and maintenance of AD. (2) Activation of Treg cells is an effective therapeutic approach for AD. (3) Many different immunomodulatory strategies activating Treg cells can provide a long-term clinical improvement of AD by induction of immune tolerance. The Treg cell-targeted immunomodulatory therapies for AD include allergen immunotherapy, microbiota, vitamin D, polyvalent human immunoglobulin G, monoclonal antibodies to the surface antigens of T cell or antigen-presenting cell, and adoptive transfer of autologous Treg cells or genetically engineered Treg cells expanded in vitro. [ABSTRACT FROM AUTHOR]

Background: Clear cell renal cell carcinoma (ccRCC) is a malignant disease containing tumor-infiltrating lymphocytes. Reactive oxygen species (ROS) are present in the tumor microenvironment and are strongly associated with cancer development. Nevertheless, the role of ROS-related genes in ccRCC remains unclear. Methods: We describe the expression patterns of ROS-related genes in ccRCC from The Cancer Genome Atlas and their alterations in genetics and transcription. An ROS-related gene signature was constructed and verified in three datasets and immunohistochemical staining (IHC) analysis. The immune characteristics of the two risk groups divided by the signature were clarified. The sensitivity to immunotherapy and targeted therapy was investigated. Results: Our signature was constructed on the basis of glutamate-cysteine ligase modifier subunit (GCLM), interaction protein for cytohesin exchange factors 1 (ICEF1), methionine sulfoxide reductase A (MsrA), and strawberry notch homolog 2 (SBNO2) genes. More importantly, protein expression levels of GCLM, MsrA, and SBNO2 were detected by IHC in our own ccRCC samples. The high-risk group of patients with ccRCC suffered lower overall survival rates. As an independent predictor of prognosis, our signature exhibited a strong association with clinicopathological features. An accurate nomogram for improving the clinical applicability of our signature was constructed. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses showed that the signature was closely related to immune response, immune activation, and immune pathways. The comprehensive results revealed that the high-risk group was associated with high infiltration of regulatory T cells and CD8+ T cells and more benefited from targeted therapy. In addition, immunotherapy had better therapeutic effects in the high-risk group. Conclusion: Our signature paved the way for assessing prognosis and developing more effective strategies of immunotherapy and targeted therapy in ccRCC. [ABSTRACT FROM AUTHOR]

Low-dose IL-2 is a promising immunotherapy in clinical trials for treating type 1 diabetes. A new IL-2 analog, IL-2/CD25 fusion protein, has been shown to more efficiently delay or prevent diabetes in NOD mice by expanding the population of activated regulatory T cells. This therapy is intended for use before clinical diagnosis, in the early stages of type 1 diabetes progression. During this prediabetic period, there is a chronic decline in β-cell function that has long-term implications for disease pathogenesis. Yet, to date, the effects of IL-2/CD25 on β-cell function have not been evaluated. In this study, we treated prediabetic NOD mice with low-dose mouse IL-2/CD25 over 5 weeks and determined its impact on β-cell function. This treatment limited the progressive impairment of glucose tolerance and insulin secretion typical of the later stages of prediabetes. Intracellular Ca2+ responses to glucose in β-cells became more robust and synchronous, indicating that changing the local immune cell infiltrate with IL-2/CD25 preserved β-cell function even after treatment cessation. Our study thus provides mechanistic insight and serves as a steppingstone for future research using low-dose IL-2/CD25 immunotherapy in patients. Article Highlights: Immunotherapies such as IL-2/CD25 are known to prevent or delay diabetes. However, their impact on individual β-cell function is not yet understood. Female NOD mice progress from stage 1 to 2 pre–type 1 diabetes between 12 and 17 weeks. Treatment with mouse IL-2 (mIL-2)/CD25 prevents this progression even after treatment cessation. Individual β-cell function (measured via intracellular Ca2+ responses to glucose) declines during the pathogenesis of type 1 diabetes. Treatment with mIL-2/CD25 therapy limits β-cell dysfunction, and function continues to improve after treatment cessation. Insulin secretion is improved with mIL-2/CD25 therapy. [ABSTRACT FROM AUTHOR]

Background: Cancer cells activate different immune checkpoint (IC) pathways in order to evade immunosurveillance. Immunotherapies involving ICs either block or stimulate these pathways and enhance the efficiency of the immune system to recognize and attack cancer cells. In this way, the development of monoclonal antibodies (mAbs) targeting ICs has significant success in cancer treatment. Recently, a systematic description of the mechanisms of action (MOA) of the mAbs has been introduced in IMGT/mAb-DB, the IMGT® database dedicated to mAbs for therapeutic applications. The characterization of these antibodies provides a comprehensive understanding of how mAbs work in cancer. Methods: In depth biocuration taking advantage of the abundant literature data as well as amino acid sequence analyses from mAbs managed in IMGT/2Dstructure-DB, the IMGT® protein database, allowed to define a standardized and consistent description of the MOA of mAbs targeting immune checkpoints in cancer therapy. Results: A fine description and a standardized graphical representation of the MOA of selected mAbs are integrated within IMGT/mAb-DB highlighting two main mechanisms in cancer immunotherapy, either Blocking or Agonist. In both cases, the mAbs enhance cytotoxic T lymphocyte (CTL)-mediated anti-tumor immune response (Immunostimulant effect) against tumor cells. On the one hand, mAbs targeting co-inhibitory receptors may have a functional Fc region to increase anti-tumor activity by effector properties that deplete Treg cells (Fceffector function effect) or may have limited FcgR binding to prevent Teff cells depletion and reduce adverse events. On the other hand, agonist mAbs targeting co-stimulatory receptors may bind to FcgRs, resulting in antibody crosslinking (FcgR crosslinking effect) and substantial agonism. Conclusion: In IMGT/mAb-DB, mAbs for cancer therapy are characterized by their chains, domains and sequence and by several therapeutic metadata, including their MOA. MOAs were recently included as a search criterion to query the database. IMGT® is continuing standardized work to describe the MOA of mAbs targeting additional immune checkpoints and novel molecules in cancer therapy, as well as expanding this study to other clinical domains. [ABSTRACT FROM AUTHOR]

Regulatory T cells (Tregs) are among the most abundant suppressive cells, which infiltrate and accumulate in the tumor microenvironment, leading to tumor escape by inducing anergy and immunosuppression. Their presence has been correlated with tumor progression, invasiveness and metastasis. Targeting tumor-associated Tregs is an effective addition to current immunotherapy approaches, but it may also trigger autoimmune diseases. The major limitation of current therapies targeting Tregs in the tumor microenvironment is the lack of selective targets. Tumor-infiltrating Tregs express high levels of cell surface molecules associated with T-cell activation, such as CTLA4, PD-1, LAG3, TIGIT, ICOS, and TNF receptor superfamily members including 4-1BB, OX40, and GITR. Targeting these molecules often attribute to concurrent depletion of antitumor effector T-cell populations. Therefore, novel approaches need to improve the specificity of targeting Tregs in the tumor microenvironment without affecting peripheral Tregs and effector T cells. In this review, we discuss the immunosuppressive mechanisms of tumor-infiltrating Tregs and the status of antibody-based immunotherapies targeting Tregs. [ABSTRACT FROM AUTHOR]

Background: Chemokines have been reported to play an important role in cancer immunotherapy. This study aimed to explore the chemokines involved in lung cancer immunotherapy. Methods: All the public data were downloaded from The Cancer Genome Atlas Program database. Quantitative real time-PCR was used to detect the mRNA level of specific molecules and Western blot was used for the protein level. Other experiments used include luciferase reporter experiments, flow cytometric analysis, Chromatin immunoprecipitation assay, ELISA and co-cultured system. Results: We found that the CCL7, CCL11, CCL14, CCL24, CCL25, CCL26, CCL28 had a higher level, while the CCL17, CCL23 had a lower level in immunotherapy non-responders. Also, we found that immunotherapy non-responders had a higher level of CD56dim NK cells, NK cells, Th1 cells, Th2 cells and Treg, yet a lower level of iDC and Th17 cells. Biological enrichment analysis indicated that in the patients with high Treg infiltration, the pathways of pancreas beta cells, KRAS signaling, coagulation, WNT BETA catenin signaling, bile acid metabolism, interferon alpha response, hedgehog signaling, PI3K/AKT/mTOR signaling, apical surface, myogenesis were significantly enriched in. CCL7, CCL11, CCL26 and CCL28 were selected for further analysis. Compared with the patients with high CCL7, CCL11, CCL26 and CCL28 expression, the patients with low CCL7, CCL11, CCL26 and CCL28 expression had a better performance of immunotherapy response and this effect might partly be due to Treg cells. Furthermore, biological exploration and clinical correlation of CCL7, CCL11, CCL26 and CCL28 were conducted, Finally, CCL28 was selected for validation. Experiments showed that under the hypoxia condition, HIF-1α was upregulated, which can directly bind to the promoter region of CCL28 and lead to its higher level. Also, CCL28 secreted by lung cancer cells could induce Tregs infiltration. Conclusion: Our study provides a novel insight focused on the chemokines in lung cancer immunotherapy. Also, CCL28 was identified as an underlying biomarker for lung cancer immunotherapy. [ABSTRACT FROM AUTHOR]

Simple Summary: This review provides a roadmap to develop safe and effective OV-based future therapeutics by using several novel synthetic and system biology strategies. Integration of system and synthetic biology can improve the genetic design of OVs backbone, maintaining enough virulence-associated genes. Furthermore, specific computation pipelines can refine target discovery in several types of cancer, identifying the MHC-I and II-restricted peptide repertoire recognized by T-cells and reinforcing anticancer immune responses. Using these versatile approaches could encourage the development of a next-generation of OVs-based therapies, overcoming current challenges such as on-target, off-tumor effects, and variable clinical responses. The efficacy and safety profile of the current OVs-based regimens could be further enhanced with additional long-lasting clinical effects. Oncolytic virus (OV)-based immunotherapy is mainly dependent on establishing an efficient cell-mediated antitumor immunity. OV-mediated antitumor immunity elicits a renewed antitumor reactivity, stimulating a T-cell response against tumor-associated antigens (TAAs) and recruiting natural killer cells within the tumor microenvironment (TME). Despite the fact that OVs are unspecific cancer vaccine platforms, to further enhance antitumor immunity, it is crucial to identify the potentially immunogenic T-cell restricted TAAs, the main key orchestrators in evoking a specific and durable cytotoxic T-cell response. Today, innovative approaches derived from systems biology are exploited to improve target discovery in several types of cancer and to identify the MHC-I and II restricted peptide repertoire recognized by T-cells. Using specific computation pipelines, it is possible to select the best tumor peptide candidates that can be efficiently vectorized and delivered by numerous OV-based platforms, in order to reinforce anticancer immune responses. Beyond the identification of TAAs, system biology can also support the engineering of OVs with improved oncotropism to reduce toxicity and maintain a sufficient portion of the wild-type virus virulence. Finally, these technologies can also pave the way towards a more rational design of armed OVs where a transgene of interest can be delivered to TME to develop an intratumoral gene therapy to enhance specific immune stimuli. [ABSTRACT FROM AUTHOR]

Summary: Immune homeostasis is heavily dependent on the action of regulatory T cells (Tregs) which act to suppress the activation of many immune cell types including autoreactive conventional T cells. A body of evidence has shown that Tregs are intrinsically defective in many common autoimmune diseases, and gene polymorphisms which increase the susceptibility of autoimmune disease development have implicated the interleukin-2 (IL-2) signaling pathway as a key dysregulated mechanism. IL-2 is essential for Treg function and survival, and Tregs are highly sensitive to low levels of this cytokine in their environment. This review will revisit the rationale behind using low-dose IL-2 as a therapy to treat autoimmune diseases and evaluate the outcomes of trials to date. Furthermore, novel engineered IL-2 therapies with increased Treg specificity have shown promise in pre-clinical studies and human clinical trials for some agents have begun. Future studies will determine whether low-dose IL-2 or engineered IL-2 therapies can change the course of autoimmune and inflammatory diseases in patients. [ABSTRACT FROM AUTHOR]

Regulatory T cells (Tregs) are a promising candidate cell therapy to treat autoimmune diseases and aid the longevity of transplanted solid organs. Despite increasing numbers of clinical trials using human Treg therapy, important questions pertaining to their in vivo fate, distribution, and function remain unanswered. Treg accumulation in relevant tissues was found to be crucial for Treg therapy efficacy, but existing blood-borne biomarkers are unlikely to accurately reflect the tissue state. Non-invasive Treg tracking by whole-body imaging is a promising alternative and can be achieved by direct radiolabelling of Tregs and following the radiolabelled cells with positron emission tomography (PET). Our goal was to evaluate the radiolabelling of polyclonal Tregs with 89Zr to permit their in vivo tracking by PET/CT for longer than one week with current preclinical PET instrumentation. We used [89Zr]Zr(oxinate)4 as the cell-labelling agent and achieved successful radiolabelling efficiency of human Tregs spanning 0.1–11.1 Bq 89Zr/Treg cell, which would be compatible with PET tracking beyond one week. We characterized the 89Zr-Tregs, assessing their phenotypes, and found that they were not tolerating these intracellular 89Zr amounts, as they failed to survive or expand in a 89Zr-dose-dependent manner. Even at 0.1 Bq 89Zr per Treg cell, while 89Zr-Tregs remained functional as determined by a five-day-long effector T cell suppression assay, they failed to expand beyond day 3 in vitro. Moreover, PET imaging revealed signs of 89Zr-Treg death after adoptive transfer in vivo. In summary, 89Zr labelling of Tregs at intracellular radioisotope amounts compatible with cell tracking over several weeks did not achieve the desired outcomes, as 89Zr-Tregs failed to expand and survive. Consequently, we conclude that indirect Treg labelling is likely to be the most effective alternative method to satisfy the requirements of this cell tracking scenario. [ABSTRACT FROM AUTHOR]

Simple Summary: In recent years, studies in cancer immunotherapy have focused on finding predictive response biomarkers to anticipate which patients will respond to each kind of treatment, optimizing treatment strategy and reducing toxicities and costs. Unfortunately, these studies are still limited, and no conclusive results have been obtained. This study was designed to prospectively analyze a cohort of lung cancer patients receiving immunotherapy attempting to determine cellular biomarkers of response, as T-lymphocyte and natural killer (NK) cell subsets, in peripheral blood. Despite previous studies, none of these populations have been identified yet with clinical relevance to be established in clinical practice. In our study, we have identified a subset of circulating CD56+CD16-PD-1+ NK cells showing a good predictive ability. These results contribute to the development of precision medicine protocols where we could stratify patients according to the expected treatment response to choose the best option for each patient. (1) Despite the effectiveness of immune checkpoint inhibitors (ICIs) in lung cancer, there is a lack of knowledge about predictive biomarkers. The objective of our study is to analyze different subsets of T-lymphocytes and natural killer (NK) cells as predictive biomarkers in a cohort of patients with nonsmall cell lung cancer (NSCLC) treated with ICI. (2) This is an observational, prospective study with 55 NSCLC patients treated with ICI. A total of 43 T and NK cell subsets are analyzed in peripheral blood, including the main markers of exhaustion, differentiation, memory, activation, and inhibition. (3) Regarding the descriptive data, Granzyme B+CD4+ Treg lymphocytes stand out (median 17.4%), and within the NK populations, most patients presented cytotoxic NK cells (CD56+CD3−CD16+GranzymeB+; median 94.8%), and about half of them have highly differentiated adaptive-like NK cells (CD56+CD3−CD16+CD57+ (mean 59.8%). A statistically significant difference was observed between the expression of PD1 within the CD56bright NK cell subpopulation (CD56+CD3−CD16−PD-1+) (p = 0.047) and a better OS. (4) Circulating immune cell subpopulations are promising prognostic biomarkers for ICI. Pending on validation with a larger sample, here we provide an analysis of the major circulating T and NK cell subsets involved in cancer immunity, with promising results despite a small sample size. [ABSTRACT FROM AUTHOR]

Background: Immune checkpoint blockade therapy with anti‐programmed cell death (PD)‐1 antibodies provides therapeutic effect for many patients of various cancers but remains inadequate in colorectal cancer (CRC) patients. The present study aims to assess the efficacy of oncolytic adenovirus (OncoAd) in enhancing the anti‐PD‐1 treatment of CRC. Methods: The estimating relative subsets of RNA transcripts algorithm was used for estimating the infiltrated immune cells in melanoma and CRC tissues. The efficacy of OncoAd with anti‐PD‐1 monotherapy was performed in a CT26 CRC mouse model in vivo. Flow cytometric analysis of peripheral blood and tumor tissues determined the difference anti‐tumor immune efficacy of OncoAd with anti‐PD‐1 monotherapy. Results: The Cancer Genome Atlas database indicated that CD8+ T cells and regulatory T cells were significantly elevated in melanoma compared to CRC cohorts. Moreover, intratumor injection of oncolytic adenovirus enhanced T cell infiltration and decreased Treg percentages in the CT26 CRC colorectal cancer mouse model. Combinatorial OncoAd with anti‐PD‐1 antibody treatment markedly enhanced the anti‐tumor efficacy of anti‐PD‐1 by significantly decreasing the tumor volume and reducing tumor growth in a CRC mouse model. To the end, OncoAd treatment increased the CD8/Treg ratio, indicating that OncoAd intratumor injection ameliorate the anti‐tumor immune response of anti‐PD‐1 therapy. Conclusion: The present study elucidates that OncoAd promotes intratumor T cell infiltration and improves anti‐PD‐1 immunotherapy, thereby providing a potent combinatorial therapeutic strategy for CRC. [ABSTRACT FROM AUTHOR]

High-risk Human papillomavirus (HPV) infections represent an important public health issue. Nearly all cervical malignancies are associated with HPV, and a range of other female and male cancers, such as anogenital and oropharyngeal. Aiming to treat HPV-related tumors, our group developed vaccines based on the genetic fusion of the HSV-1 glycoprotein D (gD) with the HPV-16 E7 oncoprotein (gDE7 vaccines). Despite the promising antitumor results reached by gDE7 vaccines in mice, combined therapies may increase the therapeutic effects by improving antitumor responses and halting immune suppressive mechanisms elicited by tumor cells. Considering cancer immunosuppressive mechanisms, indoleamine-2,3-dioxygenase (IDO) enzyme and interleukin-6 (IL-6) stand out in HPV-related tumors. Since IL-6 sustained the constitutive IDO expression, here we evaluated the therapeutic outcomes achieved by the combination of active immunotherapy based on a gDE7 protein-based vaccine with adjuvant treatments involving blocking IDO, either by use of IDO inhibitors or IL-6 knockout mice. C57BL/6 wild-type (WT) and transgenic IL-6-/- mice were engrafted with HPV16-E6/E7-expressing TC-1 cells and treated with 1-methyltryptophan isoforms (D-1MT and DL-1MT), capable to inhibit IDO. In vitro, the 1MT isoforms reduced IL-6 gene expression and IL-6 secretion in TC-1 cells. In vivo, the multi-targeted treatment improved the antitumor efficacy of the gDE7- based protein vaccine. Although the gDE7 immunization achieves partial tumor mass control in combination with D-1MT or DL-1MT in WT mice or when administered in IL-6-/- mice, the combination of gDE7 and 1MT in IL-6-/- mice further enhanced the antitumor effects, reaching total tumor rejection. The outcome of the combined therapy was associated with an increased frequency of activated dendritic cells and decreased frequencies of intratumoral polymorphonuclear myeloid-derived suppressor cells and T regulatory cells. In conclusion, the present study demonstrated that IL-6 and IDO negatively contribute to the activation of immune cells, particularly dendritic cells, reducing gDE7 vaccine-induced protective immune responses and, therefore, opening perspectives for the use of combined strategies based on inhibition of IL-6 and IDO as immunometabolic adjuvants for immunotherapies against HPVrelated tumors. [ABSTRACT FROM AUTHOR]

Allergen-specific immunotherapy (AIT) is the main treatment for allergic diseases. The therapeutic efficacy of AIT has to be improved. Neuropeptides, such as TAFA4, have immune-regulating features. The objective of this study is to promote the efficacy of AIT in experimental allergic rhinitis (AR) by the concurrent use of TAFA chemokine as a family member 4 (TAFA4). In this study, an AR mouse model was developed using ovalbumin (OVA) as the specific antigen. The AR response was assessed in mice after treatment with AIT or/and TAFA4. We found that exposure to TAFA4 activated dendritic cells (DCs) in the airway tissues. Activation of DC by TAFA4 resulted in the expression of IL-10. TAFA4 also promoted the activities of c-Maf inducing protein. The FPR1-MyD88-AKT signal pathway was associated with the TAFA4-induced Il10 expression in the DCs. Co-administration of AIT/TAFA4 attenuated the AR response in mice by inducing antigen-specific Tr1 cells. In conclusion, TAFA4 induces the expression of IL-10 in DCs. Acting as an adjuvant, TAFA4 significantly improves AIT's therapeutic efficacy against AR by inducing antigen-specific Tr1 cells. [ABSTRACT FROM AUTHOR]

Background: Chordoma is a rare, invasive, and devastating bone malignancy of residual notochord tissue that arises at the skull base, sacrum, or spine. In order to maximize immunotherapeutic approaches as a potential treatment strategy in chordoma it is important to fully characterize the tumor immune microenvironment (TIME). Multispectral immunofluorescence (MIF) allows for comprehensive evaluation of tumor compartments, molecular co-expression, and immune cell spatial relationships. Here we implement MIF to define the myeloid, T cell, and natural killer (NK) cell compartments in an effort to guide rational design of immunotherapeutic strategies for chordoma. Methods: Chordoma tumor tissue from 57 patients was evaluated using MIF. Three panels were validated to assess myeloid cell, T cell, and NK cell populations. Slides were stained using an automated system and HALO software objective analysis was utilized for quantitative immune cell density and spatial comparisons between tumor and stroma compartments. Results: Chordoma TIME analysis revealed macrophage infiltration of the tumor parenchyma at a significantly higher density than stroma. In contrast, helper T cells, cytotoxic T cells, and T regulatory cells were significantly more abundant in stroma versus tumor. T cell compartment infiltration more commonly demonstrated a tumor parenchymal exclusion pattern, most markedly among cytotoxic T cells. NK cells were sparsely found within the chordoma TIME and few were in an activated state. No immune composition differences were seen in chordomas originating from diverse anatomic sites or between those resected at primary versus advanced disease stage. Conclusion: This is the first comprehensive evaluation of the chordoma TIME including myeloid, T cell, and NK cell appraisal using MIF. Our findings demonstrate that myeloid cells significantly infiltrate chordoma tumor parenchyma while T cells tend to be tumor parenchymal excluded with high stromal infiltration. On average, myeloid cells are found nearer to target tumor cells than T cells, potentially resulting in restriction of T effector cell function. This study suggests that future immunotherapy combinations for chordoma should be aimed at decreasing myeloid cell suppressive function while enhancing cytotoxic T cell and NK cell killing. [ABSTRACT FROM AUTHOR]

Ovarian cancer, one of the most common gynecological malignancies, is characterized by high mortality and poor prognosis. Cytoreductive surgery and chemotherapy remain the mainstay of ovarian cancer treatment, and most women experience recurrence after standard care therapies. There is compelling evidence that ovarian cancer is an immunogenic tumor. For example, the accumulation of tumor-infiltrating lymphocytes is associated with increased survival, while increases in immunosuppressive regulatory T cells are correlated with poor clinical outcomes. Therefore, immunotherapies targeting components of the tumor microenvironment have been gradually integrated into the existing treatment options, including immune checkpoint blockade, adoptive cell therapy, and cancer vaccines. Immunotherapies have changed guidelines for maintenance treatment and established a new paradigm in ovarian cancer treatment. Despite single immunotherapies targeting DNA repair mechanisms, immune checkpoints, and angiogenesis bringing inspiring efficacy, only a subset of patients can benefit much from it. Thus, the multi-immunotherapy investigation remains an active area for ovarian cancer treatment. The current review provides an overview of various clinically oriented forms of multi-immunotherapy and explores potentially effective combinational therapies for ovarian cancer. [ABSTRACT FROM AUTHOR]

Regulatory T (Treg) cells play crucial roles in maintaining immune self-tolerance and immune homeostasis, and closely associated with many human diseases. Recently, Treg cells-derived extracellular vesicles (Treg-EVs) have been demonstrated as a novel cell-contact independent inhibitory mechanism of Treg cells. Treg-EVs contain many specific biological molecules, which are delivered to target cells and modulate immune responses by inhibiting T cell proliferation, inducing T cell apoptosis, and changing the cytokine expression profiles of target cells. The abnormal quantity or function of Treg-EVs is associated with several types of human diseases or conditions, such as transplant rejection, inflammatory diseases, autoimmune diseases, and cancers. Treg-EVs are promising novel potential targets for disease diagnosis, therapy, and drug transport. Moreover, Treg-EVs possess distinct advantages over Treg cell-based immunotherapies. However, the therapeutic potential of Treg-EVs is limited by some factors, such as the standardized protocol for isolation and purification, large scale production, and drug loading efficiency. In this review, we systematically describe the structure, components, functions, and basic mechanisms of action of Treg-EVs and discuss the emerging roles in pathogenesis and the potential application of Treg-EVs in human diseases. [ABSTRACT FROM AUTHOR]

Myeloid-derived suppressor cells (MDSCs) are immature cells of myeloid origin that have gained researchers' attention, as they constitute promising biomarkers and targets for novel therapeutic strategies (i.e., blockage of development, differentiation, depletion, and deactivation) in several conditions, including neoplastic, autoimmune, infective, and inflammatory diseases, as well as pregnancy, obesity, and graft rejection. They are characterised in humans by the typical immunophenotype of CD11b+CD33+HLA-DR–/low and immune-modulating properties leading to decreased T-cell proliferation, induction of T-regulatory cells (T-regs), hindering of natural killer (NK) cell functionality, and macrophage M2-polarisation. The research in the field is challenging, as there are still difficulties in defining cell-surface markers and gating strategies that uniquely identify the different populations of MDSCs, and the currently available functional assays are highly demanding. There is evidence that MDSCs display altered frequency and/or functionality and could be targeted in immune-mediated and malignant haematologic diseases, although there is a large variability of techniques and results between different laboratories. This review presents the current literature concerning MDSCs in a clinical point of view in an attempt to trigger future investigation by serving as a guide to the clinical haematologist in order to apply them in the context of precision medicine as well as the researcher in the field of experimental haematology. [ABSTRACT FROM AUTHOR]

Due to its slow progression and susceptibility to radical forms of treatment, low-grade PC is associated with high overall survival (OS). With the clinical progression of PC, the therapy is becoming more complex. The immunosuppressive tumor microenvironment (TME) makes PC a difficult target for most immunotherapeutics. Its general immune resistance is established by e.g., immune evasion through Treg cells, synthesis of immunosuppressive mediators, and the defective expression of surface neoantigens. The success of sipuleucel-T in clinical trials initiated several other clinical studies that specifically target the immune escape of tumors and eliminate the immunosuppressive properties of the TME. In the settings of PC treatment, this can be commonly achieved with radiation therapy (RT). In addition, focal therapies usually applied for localized PC, such as high-intensity focused ultrasound (HIFU) therapy, cryotherapy, photodynamic therapy (PDT), and irreversible electroporation (IRE) were shown to boost the anti-cancer response. Nevertheless, the present guidelines restrict their application to the context of a clinical trial or a prospective cohort study. This review explains how RT and focal therapies enhance the immune response. We also provide data supporting the combination of RT and focal treatments with immune therapies. [ABSTRACT FROM AUTHOR]

The discovery of immune checkpoint inhibitors (ICIs) has now been universally acknowledged as a significant breakthrough in tumor therapy after the targeted treatment of checkpoint molecules: anti-programmed cell death protein 1/programmed cell death ligand 1 (PD-1/PD-L1) and anti-cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) on several cancer types achieved satisfying results. However, there are still quite a lot of patients suffering from severe side effects and ineffective treatment outcomes. Although the current ICI therapy is far from satisfying, a series of novel immune checkpoint molecules with remarkable preclinical and clinical benefits are being widely investigated, like the V-domain Ig suppressor of T cell activation (VISTA), which can also be called PD-1 homolog (PD-1H), and ectonucleotidases: CD39, CD73, and CD38, which belong to the ribosyl cyclase family, etc. In this review, we systematically summarized and discussed these molecules' biological structures, molecular features, and the corresponding targeted drugs, aiming to help the in-depth understanding of immune checkpoint molecules and promote the clinical practice of ICI therapy. [ABSTRACT FROM AUTHOR]

Quantitative systems pharmacology (QSP) models and spatial agent-based models (ABM) are powerful and efficient approaches for the analysis of biological systems and for clinical applications. Although QSP models are becoming essential in discovering predictive biomarkers and developing combination therapies through in silico virtual trials, they are inadequate to capture the spatial heterogeneity and randomness that characterize complex biological systems, and specifically the tumor microenvironment. Here, we extend our recently developed spatial QSP (spQSP) model to analyze tumor growth dynamics and its response to immunotherapy at different spatio-temporal scales. In the model, the tumor spatial dynamics is governed by the ABM, coupled to the QSP model, which includes the following compartments: central (blood system), tumor, tumor-draining lymph node, and peripheral (the rest of the organs and tissues). A dynamic recruitment of T cells and myeloid-derived suppressor cells (MDSC) from the QSP central compartment has been implemented as a function of the spatial distribution of cancer cells. The proposed QSP-ABM coupling methodology enables the spQSP model to perform as a coarse-grained model at the whole-tumor scale and as an agent-based model at the regions of interest (ROIs) scale. Thus, we exploit the spQSP model potential to characterize tumor growth, identify T cell hotspots, and perform qualitative and quantitative descriptions of cell density profiles at the invasive front of the tumor. Additionally, we analyze the effects of immunotherapy at both whole-tumor and ROI scales under different tumor growth and immune response conditions. A digital pathology computational analysis of triple-negative breast cancer specimens is used as a guide for modeling the immuno-architecture of the invasive front. Author summary: Spatial heterogeneity is a hallmark of cancer, thus the ability to quantify the complexity of the tumor microenvironment is an important goal of computational modeling. We present a hybrid computational modeling platform, spQSP, to extend quantitative systems pharmacology (QSP) models of immuno-oncology into the spatial dimension by combining them with spatial agent-based models (ABM). We focus on several methodological and biological aspects of modeling cancer. First, the coupling of deterministic ordinary differential equation based whole-patient QSP model and stochastic, spatial agent-based model of tumor. Second, we focus on the region at the edge of the tumor called the Invasive Front (IF). We introduce a quantitative definition of IF consistent with pathologists' definition and present examples of its geometry. Third, we apply the model to immunotherapy of triple-negative breast cancer and compare the simulations of spatial distribution of immune cells (e.g., CD8+ and FoxP3+ T cells) with our recent digital pathology quantitative analysis of patients' specimens. Thus, the computational platform combines the power of QSP models with spatial ABM thus opening the way to utilizing the immense information about the tumor microenvironment contained in multiplexed pathology specimens. This modeling platform enables conducting virtual clinical trials and biomarker discovery for cancer immunotherapies. [ABSTRACT FROM AUTHOR]

The tumor microenvironment (TME) has a central role in restraining tumor growth, and a deep understanding of the interplay between cancer cells and their local environment is relevant to designing immunotherapies that fit each tumor best. Today, treatment allocation of PDAC patient is currently based on clinical, biochemical, and radiologic features but, to reach a personalized treatment, it is mandatory to identify new tools to predict tumor response and develop a more effective patient treatment. Activation of tumor-specific CD8 T cells that mediate regression of the irradiated tumor as well as a non-irradiated synchronous tumor (abscopal effect) is seen only when radiation is combined with CTLA-4 blockade, whereas each treatment alone was ineffective, demonstrating a therapeutic synergy of radiation and CTLA4 blockade. Keywords: Immunotherapy; Cancer vaccines; Checkpoint blockade agents; Adoptive immunotherapy; Targeted therapies; NIBIT EN Immunotherapy Cancer vaccines Checkpoint blockade agents Adoptive immunotherapy Targeted therapies NIBIT 1777 1786 10 06/15/22 20220701 NES 220701 Introduction Oncology embrace Immunology: the way forward captioned the XVII international meeting of the Italian Network for Tumor Biotherapy (NIBIT) held in Verona on October 11-13, 2019. [Extracted from the article]

Regulatory T cells (Treg) can impede antitumor immunity and currently represent a major obstacle to effective cancer immunotherapy. Targeting tumor-infiltrating regulatory Treg while sparing systemic Treg represents an optimal approach to this problem. Here, we provide evidence that the interleukin 23 receptor (IL23R) expressed by tumor-infiltrating Treg promotes suppressive activity. Disruption of the IL23R results in increased responsiveness of destabilized Treg to the IL12 cytokine, the production of γ-interferon, and the recruitment of CD8 T cells that inhibit tumor growth. Since the Treg destabilization pathway that is initiated by IL23R blockade is distinct and independent from the destabilization pathway coupled to glucocorticoid-induced TNFRrelated protein (GITR) activation, we examined the impact of the coordinate induction of the two destabilization pathways on antitumor immune responses. Combined GITR and IL23R antibody treatment of mice inoculated with MC38 tumors resulted in robust and synergistic antitumor responses. These findings indicate that the delineation of independent Treg destabilization pathways may allow improved approaches to the development of combination immunotherapy for cancers. [ABSTRACT FROM AUTHOR]

Type 1 diabetes (T1D) results from the destruction of pancreatic beta cells through a process that is primarily mediated by T cells. Emerging evidence suggests that dendritic cells (DCs) play a crucial role in initiating and developing this debilitating disease. DCs are professional antigen-presenting cells with the ability to integrate signals arising from tissue infection or injury that present processed antigens from these sites to naïve T cells in secondary lymphoid organs, thereby triggering naïve T cells to differentiate and modulate adaptive immune responses. Recent advancements in our knowledge of the various subsets of DCs and their cellular structures and methods of orchestration over time have resulted in a better understanding of how the T cell response is shaped. DCs employ various arsenal to maintain their tolerance, including the induction of effector T cell deletion or unresponsiveness and the generation and expansion of regulatory T cell populations. Therapies that suppress the immunogenic effects of dendritic cells by blocking T cell costimulatory pathways and proinflammatory cytokine production are currently being sought. Moreover, new strategies are being developed that can regulate DC differentiation and development and harness the tolerogenic capacity of these cells. Here, in this report, we focus on recent advances in the field of DC immunology and evaluate the prospects of DC-based therapeutic strategies to treat T1D. [ABSTRACT FROM AUTHOR]

Immune checkpoint inhibitors (ICIs) induce T-cell activation against cancer cells, and due to their anti-tumor function in multiple cancers, ICIs have been considered an important option for oncotherapy. PD-1/PD-L1 inhibitors are now widely used as ICIs for many types of cancers in clinical practices. Myocarditis induced by anti-PD-1/PD-L1 agents is uncommon but shows potentially fatal toxicity. In this review, we attempted to conclude the incidence, characteristics, diagnosis, and treatments, as well as illustrate the potential pathogenesis from the perspectives of T-lymphocyte infiltration, disturbance of regulatory T cells, cytokines, macrophage-mediated inflammatory response, and synergistic effect of PD-1/PD-L1 and CTLA4. [ABSTRACT FROM AUTHOR]