The Role of V-Domain Ig Suppressor of T Cell Activation (VISTA) in Cancer Therapy: Lessons Learned and the Road Ahead

Immune checkpoints (ICs) have pivotal roles in regulating immune responses. The inhibitory ICs in the tumor microenvironment (TME) have been implicated in the immune evasion of tumoral cells. Therefore, identifying and targeting these inhibitory ICs might be critical for eliminating tumoral cells. V-domain immunoglobulin suppressor of T cell activation (VISTA) is a novel inhibitory IC that is expressed on myeloid cells, lymphoid cells, and tumoral cells; therefore, VISTA can substantially regulate innate and adaptive anti-tumoral immune responses. Besides, growing evidence indicates that VISTA blockade can enhance the sensitivity of tumoral cells to conventional IC-based immunotherapy, e.g., cytotoxic T lymphocyte antigen 4 (CTLA-4) inhibitors. In this regard, the current study aimed to review the current evidence about the structure and expression pattern of VISTA, its role in TME, the clinicopathological significance of VISTA, and its prognostic values in various cancers. Besides, this review intended to collect the lessons from the recent pre-clinical and clinical studies and propose a strategy to overcome tumor immune-resistance states.

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Immune Checkpoints, Inhibitors and Radionuclides in Prostate Cancer: Promising Combinatorial Therapy Approach

International Journal of Molecular Sciences ◽

10.3390/ijms22084109 ◽

2021 ◽

Vol 22 (8) ◽

pp. 4109

Author(s):

Mankgopo M. Kgatle ◽

Tebatso M. G. Boshomane ◽

Ismaheel O. Lawal ◽

Kgomotso M. G. Mokoala ◽

Neo P. Mokgoro ◽

...

Keyword(s):

Prostate Cancer ◽

T Cell ◽

T Cell Activation ◽

Cell Activation ◽

Cytotoxic T Lymphocyte ◽

Cancer Control ◽

Lymphocyte Activation ◽

Immune Checkpoints ◽

Mortality And Morbidity ◽

Domain 3

Emerging research demonstrates that co-inhibitory immune checkpoints (ICs) remain the most promising immunotherapy targets in various malignancies. Nonetheless, ICIs have offered insignificant clinical benefits in the treatment of advanced prostate cancer (PCa) especially when they are used as monotherapies. Current existing PCa treatment initially offers an improved clinical outcome and overall survival (OS), however, after a while the treatment becomes resistant leading to aggressive and uncontrolled disease associated with increased mortality and morbidity. Concurrent combination of the ICIs with radionuclides therapy that has rapidly emerged as safe and effective targeted approach for treating PCa patients may shift the paradigm of PCa treatment. Here, we provide an overview of the contextual contribution of old and new emerging inhibitory ICs in PCa, preclinical and clinical studies supporting the use of these ICs in treating PCa patients. Furthermore, we will also describe the potential of using a combinatory approach of ICIs and radionuclides therapy in treating PCa patients to enhance efficacy, durable cancer control and OS. The inhibitory ICs considered in this review are cytotoxic T-lymphocyte antigen 4 (CTLA4), programmed cell death 1 (PD1), V-domain immunoglobulin suppressor of T cell activation (VISTA), indoleamine 2,3-dioxygenase (IDO), T cell Immunoglobulin Domain and Mucin Domain 3 (TIM-3), lymphocyte-activation gene 3 (LAG-3), T cell immunoreceptor with Ig and ITIM domains (TIGIT), B7 homolog 3 (B7-H3) and B7-H4.

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Regulatory mechanisms of immune checkpoints PD-L1 and CTLA-4 in cancer

Journal of Experimental & Clinical Cancer Research ◽

10.1186/s13046-021-01987-7 ◽

2021 ◽

Vol 40 (1) ◽

Author(s):

Hao Zhang ◽

Ziyu Dai ◽

Wantao Wu ◽

Zeyu Wang ◽

Nan Zhang ◽

...

Keyword(s):

T Cell ◽

T Cell Activation ◽

Cell Activation ◽

High Efficiency ◽

Cytotoxic T Lymphocyte ◽

Clinical Care ◽

Immune Checkpoints ◽

Programmed Death ◽

Programmed Death 1 ◽

Cancer Types

AbstractThe cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4)/B7 and programmed death 1 (PD-1)/ programmed cell death-ligand 1 (PD-L1) are two most representative immune checkpoint pathways, which negatively regulate T cell immune function during different phases of T-cell activation. Inhibitors targeting CTLA-4/B7 and PD1/PD-L1 pathways have revolutionized immunotherapies for numerous cancer types. Although the combined anti-CTLA-4/B7 and anti-PD1/PD-L1 therapy has demonstrated promising clinical efficacy, only a small percentage of patients receiving anti-CTLA-4/B7 or anti-PD1/PD-L1 therapy experienced prolonged survival. Regulation of the expression of PD-L1 and CTLA-4 significantly impacts the treatment effect. Understanding the in-depth mechanisms and interplays of PD-L1 and CTLA-4 could help identify patients with better immunotherapy responses and promote their clinical care. In this review, regulation of PD-L1 and CTLA-4 is discussed at the levels of DNA, RNA, and proteins, as well as indirect regulation of biomarkers, localization within the cell, and drugs. Specifically, some potential drugs have been developed to regulate PD-L1 and CTLA-4 expressions with high efficiency.

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Cytotoxic T-lymphocyte antigen-4 haplotypes and T cell activation in irritable bowel syndrome

Zeitschrift für Gastroenterologie ◽

10.1055/s-2007-988138 ◽

2007 ◽

Vol 45 (08) ◽

Author(s):

T Liebregts ◽

B Adam ◽

C Bredack ◽

S Lester ◽

S Downie-Doyle ◽

...

Keyword(s):

Irritable Bowel Syndrome ◽

T Cell ◽

T Cell Activation ◽

T Lymphocyte ◽

Cell Activation ◽

Cytotoxic T Lymphocyte ◽

Lymphocyte Antigen ◽

Irritable Bowel

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Differences in TCR repertoire and T cell activation underlie the divergent outcomes of antitumor immune responses in tumor-eradicating versus tumor-progressing hosts

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2020-001615 ◽

2021 ◽

Vol 9 (1) ◽

pp. e001615

Author(s):

Rachel A Woolaver ◽

Xiaoguang Wang ◽

Alexandra L Krinsky ◽

Brittany C Waschke ◽

Samantha M Y Chen ◽

...

Keyword(s):

T Cell ◽

Mouse Model ◽

Immune Responses ◽

Single Cell ◽

T Cell Activation ◽

Antitumor Immunity ◽

Cell Activation ◽

Tcr Repertoire ◽

Underlying Mechanisms ◽

Personalized Cancer

BackgroundAntitumor immunity is highly heterogeneous between individuals; however, underlying mechanisms remain elusive, despite their potential to improve personalized cancer immunotherapy. Head and neck squamous cell carcinomas (HNSCCs) vary significantly in immune infiltration and therapeutic responses between patients, demanding a mouse model with appropriate heterogeneity to investigate mechanistic differences.MethodsWe developed a unique HNSCC mouse model to investigate underlying mechanisms of heterogeneous antitumor immunity. This model system may provide a better control for tumor-intrinsic and host-genetic variables, thereby uncovering the contribution of the adaptive immunity to tumor eradication. We employed single-cell T-cell receptor (TCR) sequencing coupled with single-cell RNA sequencing to identify the difference in TCR repertoire of CD8 tumor-infiltrating lymphocytes (TILs) and the unique activation states linked with different TCR clonotypes.ResultsWe discovered that genetically identical wild-type recipient mice responded heterogeneously to the same squamous cell carcinoma tumors orthotopically transplanted into the buccal mucosa. While tumors initially grew in 100% of recipients and most developed aggressive tumors, ~25% of recipients reproducibly eradicated tumors without intervention. Heterogeneous antitumor responses were dependent on CD8 T cells. Consistently, CD8 TILs in regressing tumors were significantly increased and more activated. Single-cell TCR-sequencing revealed that CD8 TILs from both growing and regressing tumors displayed evidence of clonal expansion compared with splenic controls. However, top TCR clonotypes and TCR specificity groups appear to be mutually exclusive between regressing and growing TILs. Furthermore, many TCRα/TCRβ sequences only occur in one recipient. By coupling single-cell transcriptomic analysis with unique TCR clonotypes, we found that top TCR clonotypes clustered in distinct activation states in regressing versus growing TILs. Intriguingly, the few TCR clonotypes shared between regressors and progressors differed greatly in their activation states, suggesting a more dominant influence from tumor microenvironment than TCR itself on T cell activation status.ConclusionsWe reveal that intrinsic differences in the TCR repertoire of TILs and their different transcriptional trajectories may underlie the heterogeneous antitumor immune responses in different hosts. We suggest that antitumor immune responses are highly individualized and different hosts employ different TCR specificities against the same tumors, which may have important implications for developing personalized cancer immunotherapy.

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Dendritic Cell Tumor Vaccination via Fc Gamma Receptor Targeting: Lessons Learned from Pre-Clinical and Translational Studies

Vaccines ◽

10.3390/vaccines9040409 ◽

2021 ◽

Vol 9 (4) ◽

pp. 409

Author(s):

Enrique Gómez Alcaide ◽

Sinduya Krishnarajah ◽

Fabian Junker

Keyword(s):

T Cell ◽

T Cell Activation ◽

Cell Activation ◽

Tumor Antigens ◽

Checkpoint Inhibitors ◽

Critical Role ◽

Lessons Learned ◽

Antigen Delivery ◽

Tumor Vaccination ◽

Translational Studies

Despite significant recent improvements in the field of immunotherapy, cancer remains a heavy burden on patients and healthcare systems. In recent years, immunotherapies have led to remarkable strides in treating certain cancers. However, despite the success of checkpoint inhibitors and the advent of cellular therapies, novel strategies need to be explored to (1) improve treatment in patients where these approaches fail and (2) make such treatments widely and financially accessible. Vaccines based on tumor antigens (Ag) have emerged as an innovative strategy with the potential to address these areas. Here, we review the fundamental aspects relevant for the development of cancer vaccines and the critical role of dendritic cells (DCs) in this process. We first offer a general overview of DC biology and routes of Ag presentation eliciting effective T cell-mediated immune responses. We then present new therapeutic avenues specifically targeting Fc gamma receptors (FcγR) as a means to deliver antigen selectively to DCs and its effects on T-cell activation. We present an overview of the mechanistic aspects of FcγR-mediated DC targeting, as well as potential tumor vaccination strategies based on preclinical and translational studies. In particular, we highlight recent developments in the field of recombinant immune complex-like large molecules and their potential for DC-mediated tumor vaccination in the clinic. These findings go beyond cancer research and may be of relevance for other disease areas that could benefit from FcγR-targeted antigen delivery, such as autoimmunity and infectious diseases.

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Immune Restoration Diseases Reflect Diverse Immunopathological Mechanisms

Clinical Microbiology Reviews ◽

10.1128/cmr.00015-09 ◽

2009 ◽

Vol 22 (4) ◽

pp. 651-663 ◽

Cited By ~ 45

Author(s):

Patricia Price ◽

David M. Murdoch ◽

Upasna Agarwal ◽

Sharon R. Lewin ◽

Julian H. Elliott ◽

...

Keyword(s):

T Cell ◽

Immune Responses ◽

T Cell Activation ◽

Cell Activation ◽

De Novo ◽

Granulomatous Inflammation ◽

T Cell Response ◽

Immune Restoration ◽

Immunological Parameters ◽

Varicella Zoster

SUMMARY Up to one in four patients infected with human immunodeficiency virus type 1 and given antiretroviral therapy (ART) experiences inflammatory or cellular proliferative disease associated with a preexisting opportunistic infection, which may be subclinical. These immune restoration diseases (IRD) appear to result from the restoration of immunocompetence. IRD associated with intracellular pathogens are characterized by cellular immune responses and/or granulomatous inflammation. Mycobacterial and cryptococcal IRD are attributed to a pathological overproduction of Th1 cytokines. Clinicopathological characteristics of IRD associated with viral infections suggest different pathogenic mechanisms. For example, IRD associated with varicella-zoster virus or JC polyomavirus infection correlate with a CD8 T-cell response in the central nervous system. Exacerbations or de novo presentations of hepatitis associated with hepatitis C virus (HCV) infection following ART may also reflect restoration of pathogen-specific immune responses as titers of HCV-reactive antibodies rise in parallel with liver enzymes and plasma markers of T-cell activation. Correlations between immunological parameters assessed in longitudinal sample sets and clinical presentations are required to illuminate the diverse immunological scenarios described collectively as IRD. Here we present salient clinical features and review progress toward understanding their pathogeneses.

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A role for CD9 molecules in T cell activation.

Journal of Experimental Medicine ◽

10.1084/jem.184.2.753 ◽

1996 ◽

Vol 184 (2) ◽

pp. 753-758 ◽

Cited By ~ 63

Author(s):

X G Tai ◽

Y Yashiro ◽

R Abe ◽

K Toyooka ◽

C R Wood ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Immune Responses ◽

T Cell Activation ◽

Cell Activation ◽

Expression Cloning ◽

Wild Type ◽

Almost All ◽

Antigen Presenting ◽

Deficient Mice

Costimulation mediated by the CD28 molecule plays an important role in optimal activation of T cells. However, CD28-deficient mice can mount effective T cell-dependent immune responses, suggesting the existence of other costimulatory systems. In a search for other costimulatory molecules on T cells, we have developed a monoclonal antibody (mAb) that can costimulate T cells in the absence of antigen-presenting cells (APC). The molecule recognized by this mAb, 9D3, was found to be expressed on almost all mature T cells and to be a protein of approximately 24 kD molecular mass. By expression cloning, this molecule was identified as CD9, 9D3 (anti-CD9) synergized with suboptimal doses of anti-CD3 mAb in inducing proliferation by virgin T cells. Costimulation was induced by independent ligation of CD3 and CD9, suggesting that colocalization of these two molecules is not required for T cell activation. The costimulation by anti-CD9 was as potent as that by anti-CD28. Moreover, anti-CD9 costimulated in a CD28-independent way because anti-CD9 equally costimulated T cells from the CD28-deficient as well as wild-type mice. Thus, these results indicate that CD9 serves as a molecule on T cells that can deliver a potent CD28-independent costimulatory signal.

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The mouse vitronectin receptor is a T cell activation antigen.

Journal of Experimental Medicine ◽

10.1084/jem.173.2.343 ◽

1991 ◽

Vol 173 (2) ◽

pp. 343-347 ◽

Cited By ~ 36

Author(s):

K Moulder ◽

K Roberts ◽

E M Shevach ◽

J E Coligan

Keyword(s):

T Cell ◽

T Cell Activation ◽

Cell Activation ◽

Lymphoid Cells ◽

Vitronectin Receptor ◽

Cell Functions ◽

Murine Homologue ◽

Accessory Molecule ◽

T Cell Lines ◽

Activation Antigen

In this report, we demonstrate that the T cell activation antigen, recognized by monoclonal antibody H9.2B8, is the murine homologue of the vitronectin receptor (VNR) and, thereby, we provide initial evidence that VNR is expressed on lymphoid cells. VNR is expressed on a variety of T cell lines, tumors, and Con A-activated splenocytes, but not resting T cells, and is capable of binding to the extracellular matrix proteins fibronectin, fibrinogen, and vitronectin, via the tripeptide sequence RGD. There was no evidence of novel beta chains pairing with the VNR alpha chain, as has been demonstrated in some human cells. In view of recent studies demonstrating that this molecule functions as an accessory molecule in T cell activation, the VNR may play an important role in mouse T cell functions.

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CD18 Antibody Application Blocks Unwanted Off-Target T Cell Activation Caused by Bispecific Antibodies

Cancers ◽

10.3390/cancers13184596 ◽

2021 ◽

Vol 13 (18) ◽

pp. 4596

Author(s):

Joseph Kauer ◽

Fabian Vogt ◽

Ilona Hagelstein ◽

Sebastian Hörner ◽

Melanie Märklin ◽

...

Keyword(s):

T Cell ◽

T Cell Activation ◽

Cell Activation ◽

Lymphoid Cells ◽

Bispecific Antibodies ◽

Target Cells ◽

Cytokine Release ◽

Life Threatening ◽

Blocking Antibodies

T cell-recruiting bispecific antibodies (bsAbs) are successfully used for the treatment of cancer. However, effective treatment with bsAbs is so far hampered by severe side effects, i.e., potentially life-threatening cytokine release syndrome. Off-target T cell activation due to binding of bispecific CD3 antibodies to T cells in the absence of target cells may contribute to excessive cytokine release. We report here, in an in vitro setting, that off-target T cell activation is induced by bsAbs with high CD3 binding affinity and increased by endothelial- or lymphoid cells that act as stimulating bystander cells. Blocking antibodies directed against the adhesion molecules CD18/CD54 or CD2/CD58 markedly reduced this type of off-target T cell activation. CD18 blockade—in contrast to CD2—did not affect the therapeutic activity of various bsAbs. Since CD18 antibodies have been shown to be safely applicable in patients, blockade of this integrin holds promise as a potential target for the prevention of unwanted off-target T cell activation and allows the application of truly effective bsAb doses.

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