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Simple Summary: Sinonasal melanoma represents an aggressive and rare malignant tumor originating in the melanocytes of the sinonasal mucosa. The prognosis of the tumor is unfavorable and the survival rate is very low; therefore, new treatment strategies are being researched for these patients. The aim of this study was to identify all the patients diagnosed with sinonasal mucosal melanoma during a period of 15 years, and quantify the immune cells in the vicinity of the tumor using the usual hematoxylin–eosin staining method and a series of immunohistochemical reactions. Then, we classified mucosal melanomas according to their immune cells into three subtypes and correlated them with patient survival. The presence of certain tumor immune cells (eosinophils, macrophages, natural killer cells, dendritic cells) had an impact on the prognostic and immunotherapy responses of patients with melanoma and on the progression of the disease. Sinonasal mucosal melanoma originates from melanocytes and it is a rare malignancy in the sinonasal tract. It is an aggressive melanocytic neoplasm with a very poor prognosis. The symptoms are nonspecific and the diagnosis is delayed, usually until the advanced stages of the disease. The current study performs a correlation between the histopathological aspects of sinonasal mucosal melanoma and different types of immune cells present in the microenvironment, with prognostic and therapeutic implications. The endpoint is to quantify the cellular immune microenvironment and correlate it with patient survival. This study presents nine cases of primary sinonasal mucosal melanomas diagnosed at the Emergency City Hospital Timisoara, Romania during a period of 15 years. The histopathological examination was performed in the Department of Pathology of the same hospital, using morphological hematoxylin–eosin staining. Additional immunohistochemical reactions were performed to confirm the diagnosis and evaluate the components of the tumor immune microenvironment. This study identifies eosinophils, macrophages, natural killer cells and plasma cells as favorable prognostic factors. Therefore, a CD8:CD4 ratio of more than 3 is correlated with a good response to PD-1 inhibitor therapy. [ABSTRACT FROM AUTHOR]

The identification and characterization of immunogenic tumor antigens are essential for cancer vaccine development. In light of the impracticality of isolating and evaluating each putative antigen individually, in silico prediction algorithms, particularly those utilizing machine learning (ML) approaches, play a pivotal role. These algorithms significantly reduce the experimental workload necessary for discovering vaccine candidates. In this study, we employed six supervised ML methods on a dataset comprising 212 experimentally validated human tumor peptide antigens and an equal number of non-antigenic human peptides to develop models for immunogenicity prediction. These methods encompassed k-nearest neighbor (kNN), linear discriminant analysis (LDA), quadratic discriminant analysis (QDA), support vector machine (SVM), random forest (RF), and extreme gradient boosting (XGBoost). The models underwent validation through internal cross-validation within 10 groups from the training set and were further assessed using an external test set. Remarkably, the kNN model demonstrated superior performance, recognizing 90% of the known immunogens in the test set. The RF model excelled in the identification of non-immunogens, accurately classifying 93% of them in the test set. The three top-performing ML models according to multiple evaluation metrics (SVM, RF, and XGBoost) are to be subsequently integrated into the new version of the VaxiJen server, facilitating tumor antigen prediction through a majority voting mechanism. [ABSTRACT FROM AUTHOR]

Chimeric antigen receptor (CAR)-T-cell therapy has greatly improved outcomes for patients with relapsed or refractory hematological malignancies. However, challenges such as treatment resistance, relapse, and severe toxicity still hinder its widespread clinical application. Traditional transcriptome analysis has provided limited insights into the complex transcriptional landscape of both leukemia cells and engineered CAR-T-cells, as well as their interactions within the tumor microenvironment. However, with the advent of single-cell sequencing techniques, a paradigm shift has occurred, providing robust tools to unravel the complexities of these factors. These techniques enable an unbiased analysis of cellular heterogeneity and molecular patterns. These insights are invaluable for precise receptor design, guiding gene-based T-cell modification, and optimizing manufacturing conditions. Consequently, this review utilizes modern single-cell sequencing techniques to clarify the transcriptional intricacies of leukemia cells and CAR-Ts. The aim of this manuscript is to discuss the potential mechanisms that contribute to the clinical failures of CAR-T immunotherapy. We examine the biological characteristics of CAR-Ts, the mechanisms that govern clinical responses, and the intricacies of adverse events. By exploring these aspects, we hope to gain a deeper understanding of CAR-T therapy, which will ultimately lead to improved clinical outcomes and broader therapeutic applications. [ABSTRACT FROM AUTHOR]

T-cell exhaustion refers to a state of T-cell dysfunction commonly observed in chronic infections and cancer. Immune checkpoint molecules blockading using PD-1 and TIM-3 antibodies have shown promising results in reversing exhaustion, but this approach has several limitations. The treatment of T-cell exhaustion is still facing great challenges, making it imperative to explore new therapeutic strategies. With the development of nanotechnology, nanoparticles have successfully been applied as drug carriers and delivery systems in the treatment of cancer and infectious diseases. Furthermore, nanoparticle-based immunotherapy has emerged as a crucial approach to reverse exhaustion. Here, we have compiled the latest advances in T-cell exhaustion, with a particular focus on the characteristics of exhaustion that can be targeted. Additionally, the emerging nanoparticle-based delivery systems were also reviewed. Moreover, we have discussed, in detail, nanoparticle-based immunotherapies that aim to reverse exhaustion, including targeting immune checkpoint blockades, remodeling the tumor microenvironment, and targeting the metabolism of exhausted T cells, etc. These data could aid in comprehending the immunopathogenesis of exhaustion and accomplishing the objective of preventing and treating chronic diseases or cancer. [ABSTRACT FROM AUTHOR]

Chimeric antigen receptor (CAR) T-cell therapy has revolutionized the treatment of malignant and non-malignant disorders. CARs are synthetic transmembrane receptors expressed on genetically modified immune effector cells, including T cells, natural killer (NK) cells, or macrophages, which are able to recognize specific surface antigens on target cells and eliminate them. CAR-modified immune cells mediate cytotoxic antitumor effects via numerous mechanisms, including the perforin and granzyme pathway, Fas and Fas Ligand (FasL) pathway, and cytokine secretion. High hopes are associated with the prospective use of the CAR-T strategy against solid cancers, especially the ones resistant to standard oncological therapies, such as pancreatic cancer (PC). Herein, we summarize the current pre-clinical and clinical studies evaluating potential tumor-associated antigens (TAA), CAR-T cell toxicities, and their efficacy in PC. [ABSTRACT FROM AUTHOR]

Cancer management still requires more potent and safer treatments, of which immunomodulatory receptors on the lymphocyte surface have started to show promise in new cancer immunotherapies (e.g., CTLA-4 and PD-1). CD6 is a signal-transducing transmembrane receptor, mainly expressed by all T cells and some B and NK cell subsets, whose endogenous ligands (CD166/ALCAM, CD318/CDCP-1, Galectins 1 and 3) are overexpressed by malignant cells of different lineages. This places CD6 as a potential target for novel therapies against haematological and non-haematological malignancies. Recent experimental evidence for the role of CD6 in cancer immunotherapies is summarised in this review, dealing with diverse and innovative strategies from the classical use of monoclonal antibodies to soluble recombinant decoys or the adoptive transfer of immune cells engineered with chimeric antigen receptors. [ABSTRACT FROM AUTHOR]

Simple Summary: The specific mechanisms by which tumors acquire resistance to chimeric antigen receptor (CAR) T cell therapy are not completely understood. The aim of this study was to elucidate the complex interactions between tumor cells and CAR T cells targeting epithelial cell adhesion molecule (EpCAM) in a xenograft model of gastric cancer. Using whole-body CAR T cell imaging and single-cell multiomic analyses, we noticed that within resistant tumors, CAR T cells exhibited a tendency to proliferate, but they were largely dysfunctional, losing their ability to fight cancer effectively. Specifically, most CD8 T cells became exhausted within tumors, while CD4 T cells transformed into regulatory T cells that can dampen the immune response. Additionally, the resistant tumor cells had specific gene changes that could promote cancer growth and make the disease more challenging to cure. This research provides valuable information for understanding how tumors resist CAR T cell therapy and may guide future developments in cancer treatment. Epithelial cell adhesion molecule (EpCAM) is a tumor-associated antigen that is frequently overexpressed in various carcinomas. We have developed chimeric antigen receptor (CAR) T cells specifically targeting EpCAM for the treatment of gastric cancer. This study sought to unravel the precise mechanisms by which tumors evade immune surveillance and develop resistance to CAR T cell therapy. Through a combination of whole-body CAR T cell imaging and single-cell multiomic analyses, we uncovered intricate interactions between tumors and tumor-infiltrating lymphocytes (TILs). In a gastric cancer model, tumor-infiltrating CD8 T cells exhibited both cytotoxic and exhausted phenotypes, while CD4 T cells were mainly regulatory T cells. A T cell receptor (TCR) clonal analysis provided evidence of CAR T cell proliferation and clonal expansion within resistant tumors, which was substantiated by whole-body CAR T cell imaging. Furthermore, single-cell transcriptomics showed that tumor cells in mice with refractory or relapsing outcomes were enriched for genes involved in major histocompatibility complex (MHC) and antigen presentation pathways, interferon-γ and interferon-α responses, mitochondrial activities, and a set of genes (e.g., CD74, IDO1, IFI27) linked to tumor progression and unfavorable disease prognoses. This research highlights an approach that combines imaging and multiomic methodologies to concurrently characterize the evolution of tumors and the differentiation of CAR T cells. [ABSTRACT FROM AUTHOR]

Following its therapeutic effect in hematological metastasis, chimeric antigen receptor (CAR) T cell therapy has gained a great deal of attention during the last years. However, the effectiveness of this treatment has been hampered by a number of challenges, including significant toxicities, difficult access to tumor locations, inadequate therapeutic persistence, and manufacturing problems. Developing novel techniques to produce effective CARs, administer them, and monitor their anti-tumor activity in CAR-T cell treatment is undoubtedly necessary. Exploiting the advantages of nanotechnology may possibly be a useful strategy to increase the efficacy of CAR-T cell treatment. This study outlines the current drawbacks of CAR-T immunotherapy and identifies promising developments and significant benefits of using nanotechnology in order to introduce CAR transgene motifs into primary T cells, promote T cell expansion, enhance T cell trafficking, promote intrinsic T cell activity and rewire the immunosuppressive cellular and vascular microenvironments. Therefore, the development of powerful CART cells can be made possible with genetic and functional alterations supported by nanotechnology. In this review, we discuss the innovative and possible uses of nanotechnology for clinical translation, including the delivery, engineering, execution, and modulation of immune functions to enhance and optimize the anti-tumor efficacy of CAR-T cell treatment. [ABSTRACT FROM AUTHOR]

Over the past decade, Programmed Death-Ligand 1 (PD-L1) has emerged as a prominent target for cancer immunotherapies. However, its potential as an immunosuppressive therapy has been limited. In this review, we present the immunological basis of graft rejection and graft-versus-host disease (GVHD), followed by a summary of biologically relevant molecular interactions of both PD-L1 and Programmed Cell Death Protein 1 (PD-1). Finally, we present a translational perspective on how PD-L1 can interrupt alloreactive-driven processes to increase immune tolerance. Unlike most current therapies that block PD-L1 and/or its interaction with PD-1, this review focuses on how upregulation or reversed sequestration of this ligand may reduce autoimmunity, ameliorate GVHD, and enhance graft survival following organ transplant. [ABSTRACT FROM AUTHOR]

A hallmark in chronic viral infections are exhausted antigen-specific CD8+ T cell responses and the inability of the immune system to eliminate the virus. Currently, there is limited information on the variability of epitope-specific T cell exhaustion within one immune response and the relevance to the T cell receptor (TCR) repertoire. The aim of this study was a comprehensive analysis and comparison of three lymphocytic choriomeningitis virus (LCMV) epitope-specific CD8+ T cell responses (NP396, GP33 and NP205) in a chronic setting with immune intervention, e.g., immune checkpoint inhibitor (ICI) therapy, in regard to the TCR repertoire. These responses, though measured within the same mice, were individual and independent from each other. The massively exhausted NP396-specific CD8+ T cells revealed a significantly reduced TCR repertoire diversity, whereas less-exhausted GP33-specific CD8+ T cell responses were rather unaffected by chronicity in regard to their TCR repertoire diversity. NP205-specific CD8+ T cell responses showed a very special TCR repertoire with a prominent public motif of TCR clonotypes that was present in all NP205-specific responses, which separated this from NP396- and GP33-specific responses. Additionally, we showed that TCR repertoire shifts induced by ICI therapy are heterogeneous on the epitope level, by revealing profound effects in NP396-, less severe and opposed effects in NP205-, and minor effects in GP33-specific responses. Overall, our data revealed individual epitope-specific responses within one viral response that are differently affected by exhaustion and ICI therapy. These individual shapings of epitope-specific T cell responses and their TCR repertoires in an LCMV mouse model indicates important implications for focusing on epitope-specific responses in future evaluations for therapeutic approaches, e.g., for chronic hepatitis virus infections in humans. [ABSTRACT FROM AUTHOR]

Simple Summary: 5-Fluorouracil (5-FU), in combination with various therapeutic agents, is the main strategy for patients with high risk of stage 2, and advanced stages of, human colorectal cancer. Although 5-FU-based chemotherapy causes myeloid cell suppression, which has long been considered as a major adverse effect in certain cancer patients, recent studies determined that 5-FU selectively kills myeloid-derived suppressor cells (MDSCs), to increase cytotoxic T lymphocyte activation. However, the molecular mechanism underlying 5-FU's suppression of MDSCs is incompletely understood. We report here that 5-FU activates p53, to upregulate Fas expression in MDSCs, to increase MDSC sensitivity to FasL-induced apoptosis in vitro. 5-FU therapy upregulates Fas expression, to suppress MDSC accumulation, to increase CTL tumor infiltration in tumor-bearing mice. In human colorectal cancer patients, 5-FU-based chemotherapy suppresses MDSCs and increases CTLs level. Our findings determine that the p53-Fas pathway links 5-FU to MDSC suppression. Myelosuppression is a major adverse effect of 5-fluorouracil (5-FU) chemotherapy. However, recent findings indicate that 5-FU selectively suppresses myeloid-derived suppressor cells (MDSCs), to enhance antitumor immunity in tumor-bearing mice. 5-FU-mediated myelosuppression may thus have a beneficial effect for cancer patients. The molecular mechanism underlying 5-FU's suppression of MDSCs is currently unknown. We aimed at testing the hypothesis that 5-FU suppresses MDSCs through enhancing MDSC sensitivity to Fas-mediated apoptosis. We observed that, although FasL is highly expressed in T cells, Fas is weakly expressed in myeloid cells in human colon carcinoma, indicating that downregulation of Fas is a mechanism underlying myeloid cell survival and accumulation in human colon cancer. 5-FU treatment upregulated expression of both p53 and Fas, and knocking down p53 diminished 5-FU-induced Fas expression in MDSC-like cells, in vitro. 5-FU treatment also increased MDSC-like cell sensitivity to FasL-induced apoptosis in vitro. Furthermore, we determined that 5-FU therapy increased expression of Fas on MDSCs, suppressed MDSC accumulation, and increased CTL tumor infiltration in colon tumor-bearing mice. In human colorectal cancer patients, 5-FU chemotherapy decreased MDSC accumulation and increased CTL level. Our findings determine that 5-FU chemotherapy activates the p53-Fas pathway, to suppress MDSC accumulation, to increase CTL tumor infiltration. [ABSTRACT FROM AUTHOR]

While the advent of immunotherapy has revolutionized cancer treatment, its use in the treatment of glioblastoma (GBM) has been less successful. Most studies using immunotherapy in GBM have been negative and the reasons for this are still being studied. In clinical practice, interpreting response to immunotherapy has been challenging, particularly when trying to differentiate between treatment-related changes (i.e., pseudoprogression) or true tumor progression. T cell tagging is one promising technique to noninvasively monitor treatment efficacy by assessing the migration, expansion, and engagement of T cells and their ability to target tumor cells at the tumor site. [ABSTRACT FROM AUTHOR]

Despite the recent successes and durable responses with immune checkpoint inhibitors (ICI), many cancer patients, including those with melanoma, do not derive long-term benefits from ICI therapies. The lack of predictive biomarkers to stratify patients to targeted treatments has been the driver of primary treatment failure and represents an unmet medical need in melanoma and other cancers. Understanding genomic correlations with response and resistance to ICI will enhance cancer patients' benefits. Building on insights into interplay with the complex tumor microenvironment (TME), the ultimate goal should be assessing how the tumor 'instructs' the local immune system to create its privileged niche with a focus on genomic reprogramming within the TME. It is hypothesized that this genomic reprogramming determines the response to ICI. Furthermore, emerging genomic signatures of ICI response, including those related to neoantigens, antigen presentation, DNA repair, and oncogenic pathways, are gaining momentum. In addition, emerging data suggest a role for checkpoint regulators, T cell functionality, chromatin modifiers, and copy-number alterations in mediating the selective response to ICI. As such, efforts to contextualize genomic correlations with response into a more insightful understanding of tumor immune biology will help the development of novel biomarkers and therapeutic strategies to overcome ICI resistance. [ABSTRACT FROM AUTHOR]

Genetically engineered T and NK cells expressing a chimeric antigen receptor (CAR) are promising cytotoxic cells for the treatment of hematological malignancies and solid tumors. Despite the successful therapies using CAR-T cells, they have some disadvantages, such as cytokine release syndrome (CRS), neurotoxicity, or graft-versus-host-disease (GVHD). CAR-NK cells have lack or minimal cytokine release syndrome and neurotoxicity, but also multiple mechanisms of cytotoxic activity. NK cells are suitable for developing an "off the shelf" therapeutic product that causes little or no graft versus host disease (GvHD), but they are more sensitive to apoptosis and have low levels of gene expression compared to CAR-T cells. To avoid these adverse effects, further developments need to be considered to enhance the effectiveness of adoptive cellular immunotherapy. A promising approach to enhance the effectiveness of adoptive cellular immunotherapy is overcoming terminal differentiation or senescence and exhaustion of T cells. In this case, EVs derived from immune cells in combination therapy with drugs may be considered in the treatment of cancer patients, especially effector T and NK cells-derived exosomes with the cytotoxic activity of their original cells. [ABSTRACT FROM AUTHOR]

Chimeric antigen receptor (CAR) T cell immunotherapy is a revolutionary pillar in cancer treatment. Clinical experience has shown remarkable successes in the treatment of certain hematological malignancies but only limited efficacy against B cell chronic lymphocytic leukemia (CLL) and other cancer types, especially solid tumors. A wide range of engineering strategies have been employed to overcome the limitations of CAR T cell therapy. However, it has become increasingly clear that CARs have unique, unexpected features; hence, a deep understanding of how CARs signal and trigger the formation of a non-conventional immunological synapse (IS), the signaling platform required for T cell activation and execution of effector functions, would lead a shift from empirical testing to the rational design of new CAR constructs. Here, we review current knowledge of CARs, focusing on their structure, signaling and role in CAR T cell IS assembly. We, moreover, discuss the molecular features accounting for poor responses in CLL patients treated with anti-CD19 CAR T cells and propose CLL as a paradigm for diseases connected to IS dysfunctions that could significantly benefit from the development of novel CARs to generate a productive anti-tumor response. [ABSTRACT FROM AUTHOR]

T cells play central roles in the anti-tumor immunity, whose activation and differentiation are profoundly regulated by intrinsic metabolic reprogramming. Emerging evidence has revealed that metabolic processes of T cells are generally altered by tumor cells or tumor released factors, leading to crippled anti-tumor immunity. Therefore, better understanding of T cell metabolic mechanism is crucial in developing the next generation of T cell-based anti-tumor immunotherapeutics. In this review, we discuss how metabolic pathways affect T cells to exert their anti-tumor effects and how to remodel the metabolic programs to improve T cell-mediated anti-tumor immune responses. We emphasize that glycolysis, carboxylic acid cycle, fatty acid oxidation, cholesterol metabolism, amino acid metabolism, and nucleotide metabolism work together to tune tumor-reactive T-cell activation and proliferation. [ABSTRACT FROM AUTHOR]

Simple Summary: Adoptive transfer of T cells targeting tumors still remains mainly ineffective in solid entities. In this review we discuss challenges related to the tumor microenvironment (TME) and promising strategies to improve tumor control by engineering the TME or the transferred T cells themselves. T cells are important players in the antitumor immune response. Over the past few years, the adoptive transfer of genetically modified, autologous T cells—specifically redirected toward the tumor by expressing either a T cell receptor (TCR) or a chimeric antigen receptor (CAR)—has been adopted for use in the clinic. At the moment, the therapeutic application of CD19- and, increasingly, BCMA-targeting-engineered CAR-T cells have been approved and have yielded partly impressive results in hematologic malignancies. However, employing transgenic T cells for the treatment of solid tumors remains more troublesome, and numerous hurdles within the highly immunosuppressive tumor microenvironment (TME) need to be overcome to achieve tumor control. In this review, we focused on the challenges that these therapies must face on three different levels: infiltrating the tumor, exerting efficient antitumor activity, and overcoming T cell exhaustion and dysfunction. We aimed to discuss different options to pave the way for potent transgenic T cell-mediated tumor rejection by engineering either the TME or the transgenic T cell itself, which responds to the environment. [ABSTRACT FROM AUTHOR]

Unconventional T cells and innate lymphoid cells (ILCs) make up a heterogeneous set of cells that characteristically show prompt responses toward specific antigens. Unconventional T cells recognize non-peptide antigens, which are bound and presented by diverse non-polymorphic antigen-presenting molecules and comprise γδ T cells, MR1-restricted mucosal-associated invariant T cells (MAITs), and natural killer T cells (NKTs). On the other hand, ILCs lack antigen-specific receptors and act as the innate counterpart to the T lymphocytes found in the adaptive immune response. The alteration of unconventional T cells and ILCs in frequency and functionality is correlated with the onset of several autoimmune diseases, allergy, inflammation, and tumor. However, depending on the physio-pathological framework, unconventional T cells may exhibit either protective or pathogenic activity in a range of neoplastic diseases. Nonetheless, experimental models and clinical studies have displayed that some unconventional T cells are potential therapeutic targets, as well as prognostic and diagnostic markers. In fact, cell-mediated immune response in tumors has become the focus in immunotherapy against neoplastic disease. This review concentrates on the present knowledge concerning the function of unconventional T cell sets in the antitumor immune response in hematological malignancies, such as acute and chronic leukemia, multiple myeloma, and lymphoproliferative disorders. Moreover, we discuss the possibility that modulating the activity of unconventional T cells could be useful in the treatment of hematological neoplasms, in the prevention of specific conditions (such as graft versus host disease), and in the formulation of an effective anticancer vaccine therapy. The exact knowledge of the role of these cells could represent the prerequisite for the creation of a new form of immunotherapy for hematological neoplasms. [ABSTRACT FROM AUTHOR]

Accelerated glycolysis leads to secretion and accumulation of lactate and protons in the tumor environment and determines the efficacy of adoptive T cell and checkpoint inhibition therapy. Here, we analyzed effects of lactic acid on different human CD4 T cell subsets and aimed to increase CD4 T cell resistance towards lactic acid. In all CD4 T cell subsets analyzed, lactic acid inhibited metabolic activity (glycolysis and respiration), cytokine secretion, and cell proliferation. Overexpression of the lactate-metabolizing isoenzyme LDHB increased cell respiration and mitigated lactic acid effects on intracellular cytokine production. Strikingly, LDHB-overexpressing cells preferentially migrated into HCT116 tumor spheroids and displayed higher expression of cytotoxic effector molecules. We conclude, that LDHB overexpression might be a promising strategy to increase the efficacy of adoptive T cell transfer therapy. [ABSTRACT FROM AUTHOR]

Cancer immunotherapy has achieved multiple clinical benefits and has become an indispensable component of cancer treatment. Targeting tumor-specific antigens, also known as neoantigens, plays a crucial role in cancer immunotherapy. T cells of adaptive immunity that recognize neoantigens, but do not induce unwanted off-target effects, have demonstrated high efficacy and low side effects in cancer immunotherapy. Tumor neoantigens derived from accumulated genetic instability can be characterized using emerging technologies, such as high-throughput sequencing, bioinformatics, predictive algorithms, mass-spectrometry analyses, and immunogenicity validation. Neoepitopes with a higher affinity for major histocompatibility complexes can be identified and further applied to the field of cancer vaccines. Therapeutic vaccines composed of tumor lysates or cells and DNA, mRNA, or peptides of neoantigens have revoked adaptive immunity to kill cancer cells in clinical trials. Broad clinical applicability of these therapeutic cancer vaccines has emerged. In this review, we discuss recent progress in neoantigen identification and applications for cancer vaccines and the results of ongoing trials. [ABSTRACT FROM AUTHOR]

Simple Summary: Tumor immune evasion is mediated in large part by the inhibition of anti-tumor T cell responses. Both the induction of tumor antigen-specific T cells and the activation state of T effector cells may be attenuated by surface receptors, which upon binding to counter receptors on immunoregulatory cell types and tumor cells, induce inhibitory T cell signaling. Immune checkpoint inhibitors (ICI) are antibodies that block interaction of these receptor pairs and thereby prevent T cell inhibition. Only a small percentage of tumor patients are responsive to treatment with ICI, which on the one hand raises the issue of possible reasons for failure, and on the other hand has spurred the development of additional ICI targeting other T cell inhibitory receptors. Our review aims to summarize knowledge on the functional role of these (inhibitory) receptors by additional types of leukocytes, and consequences of receptor blockade by ICI as a potential cause for unwanted side effects limiting the success of therapy. Deeper knowledge in this regard is a prerequisite for the development of more refined combination therapies. The approval of immune checkpoint inhibitors (ICI) that serve to enhance effector T-cell anti-tumor responses has strongly improved success rates in the treatment of metastatic melanoma and other tumor types. The currently approved ICI constitute monoclonal antibodies blocking cytotoxic T-lymphocyte-associated protein (CTLA)-4 and anti-programmed cell death (PD)-1. By this, the T-cell-inhibitory CTLA-4/CD80/86 and PD-1/PD-1L/2L signaling axes are inhibited. This leads to sustained effector T-cell activity and circumvents the immune evasion of tumor cells, which frequently upregulate PD-L1 expression and modulate immune checkpoint molecule expression on leukocytes. As a result, profound clinical responses are observed in 40–60% of metastatic melanoma patients. Despite the pivotal role of T effector cells for triggering anti-tumor immunity, mounting evidence indicates that ICI efficacy may also be attributable to other cell types than T effector cells. In particular, emerging research has shown that ICI also impacts innate immune cells, such as myeloid cells, natural killer cells and innate lymphoid cells, which may amplify tumoricidal functions beyond triggering T effector cells, and thus improves clinical efficacy. Effects of ICI on non-T cells may additionally explain, in part, the character and extent of adverse effects associated with treatment. Deeper knowledge of these effects is required to further develop ICI treatment in terms of responsiveness of patients to treatment, to overcome resistance to ICI and to alleviate adverse effects. In this review we give an overview into the currently known immunomodulatory effects of ICI treatment in immune cell types other than the T cell compartment. [ABSTRACT FROM AUTHOR]

Simple Summary: Despite tremendous treatment efforts, cancer is still one of the leading causes of death, with approximately 10 million deaths in 2020. In the last decade, immunotherapy entered the stage of clinical practice and was added to the established regimen, i.e., surgery, chemo- and radiation therapy, to fight this deadly disease. Cancer immunotherapies, including immune checkpoint inhibitors, target malignant cancer cells and immune cells in the tumor micro-environment. Among those cells are T cells and antigen-presenting cells, which can efficiently control tumors via both cell-cell interactions and by secretion of inflammatory cytokines. The presence of specific cytokines in the tumor microenvironment has been shown to induce senescence in tumor cells. Subsequently, tumor cells acquire a senescence-associated secretory phenotype that strongly modulates anti-tumor responses. This review describes the mechanisms of cytokine-induced senescence in the tumor microenvironment and highlights their relevance for therapeutic perspectives. In contrast to surgical excision, chemotherapy or radiation therapy, immune checkpoint blockade therapies primarily influence cells in the tumor microenvironment, especially the tumor-associated lymphocytes and antigen-presenting cells. Besides complete remission of tumor lesions, in some patients, early tumor regression is followed by a consolidation phase where residing tumors remain dormant. Whereas the cytotoxic mechanisms of the regression phase (i.e., apoptosis, necrosis, necroptosis, and immune cell-mediated cell death) have been extensively described, the mechanisms underlying the dormant state are still a matter of debate. Here, we propose immune-mediated induction of senescence in cancers as one important player. Senescence can be achieved by tumor-associated antigen-specific T helper 1 cells, cytokines or antibodies targeting immune checkpoints. This concept differs from cytotoxic treatment, which often targets the genetic makeup of cancer cells. The immune system's ability to establish "defensive walls" around tumors also places the tumor microenvironment into the fight against cancer. Those "defensive walls" isolate the tumor cells instead of increasing the selective pressure. They also keep the tumor cells in a non-proliferating state, thereby correcting the derailed tissue homeostasis. In conclusion, strengthening the senescence surveillance of tumors by the immune cells of the microenvironment is a future goal to dampen this life-threatening disease. [ABSTRACT FROM AUTHOR]

The clinical benefits of immune checkpoint blockage (ICB) therapy have been widely reported. In patients with cancer, researchers have demonstrated the clinical potential of antitumor cytotoxic T cells that can be reinvigorated or enhanced by ICB. Compared to self-antigens, neoantigens derived from tumor somatic mutations are believed to be ideal immune targets in tumors. Candidate tumor neoantigens can be identified through immunogenomic or immunopeptidomic approaches. Identification of neoantigens has revealed several points of the clinical relevance. For instance, tumor mutation burden (TMB) may be an indicator of immunotherapy. In various cancers, mutation rates accompanying neoantigen loads may be indicative of immunotherapy. Furthermore, mismatch repair-deficient tumors can be eradicated by T cells in ICB treatment. Hence, immunotherapies using vaccines or adoptive T-cell transfer targeting neoantigens are potential innovative strategies. However, significant efforts are required to identify the optimal epitopes. In this review, we summarize the recent progress in the identification of neoantigens and discussed preclinical and clinical studies based on neoantigens. We also discuss the issues remaining to be addressed before clinical applications of these new therapeutic strategies can be materialized. [ABSTRACT FROM AUTHOR]

Treatment for Hodgkin lymphoma (HL) has evolved considerably from the time it was originally described in the 19th century with many patients now being cured with frontline therapy. Despite these advances, upwards of 10% of patients experience progressive disease after initial therapy with an even higher percentage relapsing. Until recently there had been limited therapeutic options for relapsed and/or refractory HL outside of highly intensive chemotherapy with stem cell rescue. Improved understanding of the pathophysiology of HL, coupled with the emergence of more targeted therapeutics, has reshaped how we view the treatment of relapsed/refractory HL and its prognosis. With this, there has been an increased focus on immunotherapies that can reprogram the immune system to better overcome the immunosuppressive milieu found in HL for improved cancer cell killing. In particular, chimeric antigen receptor (CAR) T cells are emerging as a valuable therapeutic tool in this area. Building on the success of antibody-drug conjugates directed against CD30, CAR T cells engineered to recognize the same antigen are now reaching patients. Though still in its infancy, CAR T therapy for relapsed/refractory HL has shown exceptional promise in early-stage clinical trials with the potential for durable responses even in patients who had progressed through multiple lines of prior therapy. Here we will review currently available data on the use of CAR T cells in HL, strategies to optimize their effectiveness, and how this therapy may fit into the treatment paradigm of HL going forward. [ABSTRACT FROM AUTHOR]

Acute myeloid leukemia (AML) is a heterogeneous disease associated with various alterations in T cell phenotype and function leading to an abnormal cell population, ultimately leading to immune exhaustion. However, restoration of T cell function allows for the execution of cytotoxic mechanisms against leukemic cells in AML patients. Therefore, long-term disease control, which requires multiple therapeutic approaches, includes those aimed at the re-establishment of cytotoxic T cell activity. AML treatments that harness the power of T lymphocytes against tumor cells have rapidly evolved over the last 3 to 5 years through various stages of preclinical and clinical development. These include tissue-infiltrated lymphocytes (TILs), bispecific antibodies, immune checkpoint inhibitors (ICIs), chimeric antigen receptor T (CAR-T) cell therapy, and tumor-specific T cell receptor gene-transduced T (TCR-T) cells. In this review, these T cell-based immunotherapies and the potential of TILs as a novel antileukemic therapy will be discussed. [ABSTRACT FROM AUTHOR]

Simple Summary: Immunotherapy is a rapidly advancing field in breast cancer treatment, however, it encounters many obstacles that leave open gateways for breast cancer cells to resist novel immunotherapies. It is believed that the tumor microenvironment consisting of cancer, stromal, and immune cells as well as a plethora of tumor-promoting soluble factors, is responsible for the failure of therapeutic strategies in cancer, including breast tumors. Therefore, an in-depth understanding of key barriers to effective immunotherapy, focusing the research efforts on harnessing the power of the immune system, and thus, developing new strategies to overcome the resistance may contribute significantly to increase breast cancer patient survival. In this review, we discuss the latest reports regarding the strategies rendering the immunosuppressive tumor microenvironment more sensitive to immunotherapy in breast cancers, HER2-positive and triple-negative types of breast cancer, which are attractive from an immunotherapeutic point of view. Breast cancer (BC) has traditionally been considered to be not inherently immunogenic and insufficiently represented by immune cell infiltrates. Therefore, for a long time, it was thought that the immunotherapies targeting this type of cancer and its microenvironment were not justified and would not bring benefits for breast cancer patients. Nevertheless, to date, a considerable number of reports have indicated tumor-infiltrating lymphocytes (TILs) as a prognostic and clinically relevant biomarker in breast cancer. A high TILs expression has been demonstrated in primary tumors, of both, HER2-positive BC and triple-negative (TNBC), of patients before treatment, as well as after treatment with adjuvant and neoadjuvant chemotherapy. Another milestone was reached in advanced TNBC immunotherapy with the help of the immune checkpoint inhibitors directed against the PD-L1 molecule. Although those findings, together with the recent developments in chimeric antigen receptor T cell therapies, show immense promise for significant advancements in breast cancer treatments, there are still various obstacles to the optimal activity of immunotherapeutics in BC treatment. Of these, the immunosuppressive tumor microenvironment constitutes a key barrier that greatly hinders the success of immunotherapies in the most aggressive types of breast cancer, HER2-positive and TNBC. Therefore, the improvement of the current and the demand for the development of new immunotherapeutic strategies is strongly warranted. [ABSTRACT FROM AUTHOR]

Despite the important evolution of immunotherapeutic agents, brain tumors remain, in general, refractory to immune therapeutics. Recent discoveries have revealed that the glioma microenvironment includes a wide variety of immune cells in various states that play an important role in the process of tumorigenesis. Anti-tumor immune activity may be occurring or induced in immunogenic hot spots or at the invasive edge of central nervous system (CNS) tumors. Understanding the complex heterogeneity of the immune microenvironment in gliomas will likely be the key to unlocking the full potential of immunotherapeutic strategies. An essential consideration will be the induction of immunological effector responses in the setting of the numerous aspects of immunosuppression and evasion. As such, immune therapeutic combinations are a fundamental objective for clinical studies in gliomas. Through immune profiling conducted on immune competent murine models of glioma and ex vivo human glioma tissue, we will discuss how the frequency, distribution of immune cells within the microenvironment, and immune modulatory processes, may be therapeutically modulated to lead to clinical benefits. [ABSTRACT FROM AUTHOR]

Epithelial ovarian cancer (EOC) is one of the most common causes of cancer-related deaths among women and is associated with age and age-related diseases. With increasing evidence of risks associated with metabolic inflammatory conditions, such as obesity and type 2 diabetes mellitus (T2DM), it is important to understand the complex pathophysiological mechanisms underlying cancer progression and metastasis. Age-related conditions can lead to both genotypic and phenotypic immune function alterations, such as induction of senescence, which can contribute to disease progression. Immune senescence is a common phenomenon in the ageing population, which is now known to play a role in multiple diseases, often detrimentally. EOC progression and metastasis, with the highest rates in the 75–79 age group in women, have been shown to be influenced by immune cells within the "milky spots" or immune clusters of the omentum. As T2DM has been reported to cause T cell senescence in both prediabetic and diabetic patients, there is a possibility that poor prognosis in EOC patients with T2DM is partly due to the accumulation of senescent T cells in the omentum. In this review, we explore this hypothesis with recent findings, potential therapeutic approaches, and future directions. [ABSTRACT FROM AUTHOR]

It is now well accepted that the immune system can control cancer growth. However, tumors escape immune-mediated control through multiple mechanisms and the downregulation or loss of major histocompatibility class (MHC)-I molecules is a common immune escape mechanism in many cancers. MHC-I molecules present antigenic peptides to cytotoxic T cells, and MHC-I loss can render tumor cells invisible to the immune system. In this review, we examine the dysregulation of MHC-I expression in cancer, explore the nature of MHC-I-bound antigenic peptides recognized by immune cells, and discuss therapeutic strategies that can be used to overcome MHC-I deficiency in solid tumors, with a focus on the role of natural killer (NK) cells and CD4 T cells. [ABSTRACT FROM AUTHOR]

The understanding of the tumor microenvironment (TME) has been expanding in recent years in the context of interactions among different cell types, through direct cell–cell communication as well as through soluble factors. It has become evident that the development of a successful antitumor response depends on several TME factors. In this context, the number, type, and subsets of immune cells, as well as the functionality, memory, and exhaustion state of leukocytes are key factors of the TME. Both the presence and functionality of immune cells, in particular T cells, are regulated by cellular and soluble factors of the TME. In this regard, one fundamental reason for failure of antitumor responses is hijacked immune cells, which contribute to the immunosuppressive TME in multiple ways. Specifically, reactive oxygen species (ROS), metabolites, and anti-inflammatory cytokines have central roles in generating an immunosuppressive TME. In this review, we focused on recent developments in the immune cell constituents of the TME, and the micromilieu control of antitumor responses. Furthermore, we highlighted the current challenges of T cell-based immunotherapies and potential future strategies to consider for strengthening their effectiveness. [ABSTRACT FROM AUTHOR]

Simple Summary: The mortality of hepatocellular carcinoma (HCC) is quickly increasing worldwide. Immunotherapy enables the immune defense of the organism to target liver cancer cells. Recent technologies enable engineering of immune cells, and notably T lymphocytes, to make them more efficient against the tumor. These technics (called TCR engineered T cells and CAR-T cells) are promising and are actually tested in clinical trials. This review explains the concept of TCR modified and CAR-T cells in liver cancer (targets and mechanisms of action) and reports the results from recent clinical trials. The mortality of hepatocellular carcinoma (HCC) is quickly increasing worldwide. In unresectable HCC, the cornerstone of systemic treatments is switching from tyrosine kinase inhibitors to immune checkpoints inhibitors (ICI). Next to ICI, adoptive cell transfer represents another promising field of immunotherapy. Targeting tumor associated antigens such as alpha-fetoprotein (AFP), glypican-3 (GPC3), or New York esophageal squamous cell carcinoma-1 (NY-ESO-1), T cell receptor (TCR) engineered T cells and chimeric antigen receptors (CAR) engineered T cells are emerging as potentially effective therapies, with objective responses reported in early phase trials. In this review, we address the biological rationale of TCR/CAR engineered T cells in advanced HCC, their mechanisms of action, and results from recent clinical trials. [ABSTRACT FROM AUTHOR]

Simple Summary: Cancer immunology is a rapidly evolving field. In this context, this review article has three objectives. First, to explain the genomic origin of tumor antigens and to emphasize that many of them are encoded by unconventional RNAs. Second, to discuss the inherent limitations of all strategies aimed at discovering tumor antigens, and to highlight the importance of using mass spectrometry validation for each antigen considered for clinical trials. Third, to explain that many tumor antigens are not spontaneously detected by the immune system, because they are not presented adequately by dendritic cells. Concepts presented in this article must be taken into account in the design of cancer immunotherapies and of cancer vaccines in particular. The dominant paradigm holds that spontaneous and therapeutically induced anti-tumor responses are mediated mainly by CD8 T cells and directed against tumor-specific antigens (TSAs). The presence of specific TSAs on cancer cells can only be proven by mass spectrometry analyses. Bioinformatic predictions and reverse immunology studies cannot provide this type of conclusive evidence. Most TSAs are coded by unmutated non-canonical transcripts that arise from cancer-specific epigenetic and splicing aberrations. When searching for TSAs, it is therefore important to perform mass spectrometry analyses that interrogate not only the canonical reading frame of annotated exome but all reading frames of the entire translatome. The majority of aberrantly expressed TSAs (aeTSAs) derive from unstable short-lived proteins that are good substrates for direct major histocompatibility complex (MHC) I presentation but poor substrates for cross-presentation. This is an important caveat, because cancer cells are poor antigen-presenting cells, and the immune system, therefore, depends on cross-presentation by dendritic cells (DCs) to detect the presence of TSAs. We, therefore, postulate that, in the untreated host, most aeTSAs are undetected by the immune system. We present evidence suggesting that vaccines inducing direct aeTSA presentation by DCs may represent an attractive strategy for cancer treatment. [ABSTRACT FROM AUTHOR]

In the past 20 years, the immune system has increasingly been recognized as a major player in tumor cell control, leading to considerable advances in cancer treatment. While promising with regards to melanoma, renal cancer and non-small cell lung cancer, immunotherapy provides, for the time being, limited success in other cancers, including ovarian cancer, potentially due to insufficient immunogenicity or to a particularly immunosuppressive microenvironment. In this review, we provide a global description of the immune context of ovarian cancer, in particular epithelial ovarian cancer (EOC). We describe the adaptive and innate components involved in the EOC immune response, including infiltrating tumor-specific T lymphocytes, B lymphocytes, and natural killer and myeloid cells. In addition, we highlight the rationale behind the use of EOC preclinical mouse models to assess resistance to immunotherapy, and we summarize the main preclinical studies that yielded anti-EOC immunotherapeutic strategies. Finally, we focus on major published or ongoing immunotherapy clinical trials concerning EOC. [ABSTRACT FROM AUTHOR]

Outcome in high-risk patients with refractory or relapsed germ cell tumours (GCT) remains poor. Novel strategies enhancing therapeutic efficacy whilst limiting therapeutic burden are warranted, yet immunotherapy approaches geared towards activating endogenous antitumor responses have not been successful thus far. Redirection of cytotoxic effector cells by bispecific antibodies represents a promising approach in this setting. We demonstrate that the Epithelial Cell Adhesion Molecule (EpCAM) is broadly expressed in GCT cell lines of different histologic origin including seminoma, choriocarcinoma (CHC), and embryonal carcinoma (EC). In these GCT lines of variable EpCAM surface expression, targeting T cells by the prototypic bispecific EpCAM/CD3-antibody (bAb) Catumaxomab together with natural killer (NK) cell engagement via the Fc domain promotes profound cytotoxicity across a broad range of antibody dilutions. In contrast, tumor cell lysis mediated by either immune cell subset alone is influenced by surface density of the target antigen. In the CHC line JAR, NK cell-dependent cytotoxicity dominates, which may be attributed to differential surface expression of immunomodulatory proteins such as MHC-I, CD24, and Fas receptors on CHC and EC. In view of redirecting T cell therapy mediated by bispecific antibodies, such differences in GCT immunophenotype potentially favoring immune escape are worth further investigation. [ABSTRACT FROM AUTHOR]

Background: The immune microenvironment plays a role in tumorigenesis. Chronic Obstructive Pulmonary Disease (COPD) is an independent risk factor for lung cancer (LC). We hypothesized that immune profile characterized by T regulatory (Treg), natural killer (NK), and plasma cells, as well as interleukin (IL)-10 and interferon-gamma, may differ within tumors of LC patients with/without COPD. Methods: Treg (anti-CD3 and anti-forkhead boxP3 antibodies), NK (anti-NCR1 antibody), IgG (anti-CD138-IgG antibody), IgA (anti-CD138-IgA antibody) using immunohistochemistry, and both IL-10 and interferon-gamma (ELISA) were quantified in tumor and non-tumor specimens (thoracotomy for lung tumor resection) from 33 LC–COPD patients and 20 LC-only patients. Results: Immune profile in tumor versus non-tumor specimens: Treg cell counts significantly increased in tumors of both LC and LC–COPD patients, while in tumors of the latter group, IgG-secreting plasma cells significantly decreased and IL-10 increased. No significant differences were seen in levels of NK cells, IgA-secreting cells, IgA/IgG, or interferon-gamma. Immune profile in tumors of LC–COPD versus LC: No significant differences were observed in tumors between LC–COPD and LC patients for any study marker. Conclusions: Immune cell subtypes and cytokines are differentially expressed in lung tumors, and the presence of COPD elicited a decline in IgG-secreting plasma cell levels but not in other cell types. [ABSTRACT FROM AUTHOR]

Chimeric antigen receptor (CAR) gene-modified T cells (CAR T cells) can eradicate B cell malignancies via recognition of surface-expressed B lineage antigens. Antigen escape remains a major mechanism of relapse and is a key barrier for expanding the use of CAR T cells towards solid cancers with their more diverse surface antigen repertoires. In this review we discuss strategies by which cancers become amenable to effective CAR T cell therapy despite heterogeneous phenotypes. Pharmaceutical approaches have been reported that selectively upregulate individual target antigens on the cancer cell surface to sensitize antigen-negative subclones for recognition by CARs. In addition, advanced T cell engineering strategies now enable CAR T cells to interact with more than a single antigen simultaneously. Still, the choice of adequate targets reliably and selectively expressed on the cell surface of tumor cells but not normal cells, ideally by driving tumor growth, is limited, and even dual or triple antigen targeting is unlikely to cure most solid tumors. Innovative receptor designs and combination strategies now aim to recruit bystander cells and alternative cytolytic mechanisms that broaden the activity of CAR-engineered T cells beyond CAR antigen-dependent tumor cell recognition. [ABSTRACT FROM AUTHOR]

Immune checkpoint inhibitor (ICI) therapy has shown extraordinary promise at treating cancers otherwise resistant to treatment. However, for ICI therapy to be effective, it must overcome the metabolic limitations of the tumor microenvironment. Tumor metabolism has long been understood to be highly dysregulated, with potent immunosuppressive effects. Moreover, T cell activation and longevity within the tumor microenvironment are intimately tied to T cell metabolism and are required for the long-term efficacy of ICI therapy. We discuss in this review the intersection of metabolic competition in the tumor microenvironment, T cell activation and metabolism, the roles of tumor cell metabolism in immune evasion, and the impact of host metabolism in determining immune surveillance and ICI therapy outcomes. We also discussed the effects of obesity and calorie restriction—two important systemic metabolic perturbations that impact intrinsic metabolic pathways in T cells as well as cancer cells. [ABSTRACT FROM AUTHOR]

Immune cell infiltrates within the tumor microenvironment can influence treatment response and outcome in several cancers. In this study, we developed RNA-based immune signatures from pan-cancer analysis that could serve as potential markers across tumor types and tested them for association with outcome in high-grade serous ovarian cancer (HGSOC) and other female cancers. Pan-cancer RNA-Seq cluster analysis of immune-related gene expression profiles in The Cancer Genome Atlas (TCGA) from 29 different solid tumors (4446 specimens) identified distinct but concordant gene signatures. Among these immune signatures, Cytotoxic Lymphocyte Immune Signature (CLIS), T-cell trafficking (TCT), and the TCT to M2 tumor-associated macrophage (M2TAM) ratio (TCT:M2TAM) were significantly (p < 0.05) associated with overall survival (OS), using multivariable Cox proportional hazards regression models, in a discovery cohort and two independent validation cohorts of HGSOC patients. Notably, the TCT:M2TAM ratio was highly significant (p ≤ 0.000001) in two HGSOC cohorts. Immune signatures were also significant (p < 0.05) in the presence of tumor cytoreduction, BRCA1/2 mutation, and COL2A1 expression. Importantly, the CLIS and TCT signatures were also validated for prognostic significance (p < 0.05) in TCGA cohorts for endometrial and high tumor mutational burden (Hi-TMB) breast cancer. These immune signatures also have the potential for being predictive in other cancers and for patients following different treatment strategies. [ABSTRACT FROM AUTHOR]

Increasing evidence suggests that the immune system plays a dynamic role in the progression of ovarian cancer, the deadliest gynecological malignancy worldwide. Accumulation of tumor-infiltrating lymphocytes has been associated with increased survival in ovarian cancer patients, and diverse interactions among immune cells in the tumor microenvironment determine tumor progression. While the regulatory functions of T cells among tumor-infiltrating lymphocytes are well defined and also involve therapeutic interventions, the role of B cells in ovarian cancer progression is still limited to their impact on survival. Recent studies have identified both pro- and anti-tumor responses of B cells in solid tumors, as different subsets of B cells play diverse roles in progression. Thus, in-depth characterization of B cell subtypes in each disease stage is crucial for understanding the importance and therapeutic potential of these cells in ovarian cancer. In this review, we summarize current knowledge about B cells in ovarian cancer and discuss emerging therapeutic interventions that could harness B cells to combat this deadly disease. [ABSTRACT FROM AUTHOR]

Programmed cell death-1 (PD-1) is a cell surface receptor that dampens adaptive immune responses. PD-1 is activated by the engagement of its ligands PDL-1 or PDL-2. This results in the inhibition of T cell proliferation, differentiation, cytokine secretion, and cytolytic function. Although a great deal is known about PD-1 mediated regulation of CD4+ and CD8+ T cells, its expression and function in innate lymphoid cells (ILCs) are yet to be fully deciphered. This review summarizes the role of PD-1 in (1) modulating ILC development, (2) ILC function, and (3) PD-1 signaling in ILC. Finally, we explore how PD-1 based immunotherapies may be beneficial in boosting ILC responses in cancer, infections, and other immune-related disorders. [ABSTRACT FROM AUTHOR]

Effective adoptive T cell therapy (ACT) comprises the killing of cancer cells through the therapeutic use of transferred T cells. One of the main ACT approaches is chimeric antigen receptor (CAR) T cell therapy. CAR T cells mediate MHC-unrestricted tumor cell killing by enabling T cells to bind target cell surface antigens through a single-chain variable fragment (scFv) recognition domain. Upon engagement, CAR T cells form a non-classical immune synapse (IS), required for their effector function. These cells then mediate their anti-tumoral effects through the perforin and granzyme axis, the Fas and Fas ligand axis, as well as the release of cytokines to sensitize the tumor stroma. Their persistence in the host and functional outputs are tightly dependent on the receptor's individual components—scFv, spacer domain, and costimulatory domains—and how said component functions converge to augment CAR T cell performance. In this review, we bring forth the successes and limitations of CAR T cell therapy. We delve further into the current understanding of how CAR T cells are designed to function, survive, and ultimately mediate their anti-tumoral effects. [ABSTRACT FROM AUTHOR]