Perspectives on the Role of T Cell Negative Immune Checkpoint Receptors in Health and Disease

2020 ◽  
pp. 297-318
Author(s):  
Tsuyoshi Fujita ◽  
Danielle M. Clements ◽  
Thomas A. Premeaux ◽  
Lishomwa C. Ndhlovu
Keyword(s):  
T Cell ◽  
Immune Checkpoint ◽  
Health And Disease ◽  
Checkpoint Receptors

scholarly journals Rethinking immune checkpoint blockade: ‘Beyond the T cell’

2021 ◽  
Vol 9 (1) ◽  
pp. e001460 ◽  
Author(s):  
Xiuting Liu ◽  
Graham D Hogg ◽  
David G DeNardo
Keyword(s):  
Immune System ◽  
T Cell ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Antitumor Immunity ◽  
Checkpoint Inhibitors ◽  
Clinical Success ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade

The clinical success of immune checkpoint inhibitors has highlighted the central role of the immune system in cancer control. Immune checkpoint inhibitors can reinvigorate anti-cancer immunity and are now the standard of care in a number of malignancies. However, research on immune checkpoint blockade has largely been framed with the central dogma that checkpoint therapies intrinsically target the T cell, triggering the tumoricidal potential of the adaptive immune system. Although T cells undoubtedly remain a critical piece of the story, mounting evidence, reviewed herein, indicates that much of the efficacy of checkpoint therapies may be attributable to the innate immune system. Emerging research suggests that T cell-directed checkpoint antibodies such as anti-programmed cell death protein-1 (PD-1) or programmed death-ligand-1 (PD-L1) can impact innate immunity by both direct and indirect pathways, which may ultimately shape clinical efficacy. However, the mechanisms and impacts of these activities have yet to be fully elucidated, and checkpoint therapies have potentially beneficial and detrimental effects on innate antitumor immunity. Further research into the role of innate subsets during checkpoint blockade may be critical for developing combination therapies to help overcome checkpoint resistance. The potential of checkpoint therapies to amplify innate antitumor immunity represents a promising new field that can be translated into innovative immunotherapies for patients fighting refractory malignancies.

501 VISTA regulates the differentiation and suppressive function of myeloid-derived suppressor cells

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A536-A536
Author(s):  
Juan Dong ◽  
Cassandra Gilmore ◽  
Hieu Ta ◽  
Keman Zhang ◽  
Sarah Stone ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Signaling Pathways ◽  
Immune Checkpoint ◽  
Suppressor Cells ◽  
Myeloid Cell ◽  
Myeloid Derived Suppressor Cells ◽  
Checkpoint Protein ◽  
Suppressive Function

BackgroundV-domain immunoglobulin suppressor of T cell activation (VISTA) is a B7 family inhibitory immune checkpoint protein and is highly expressed on myeloid cells and T cells.1 VISTA acts as both an inhibitory ligand when expressed on antigen-presenting cells and a receptor when expressed on T cells. Our recent study has shown that VISTA is a myeloid cell-specific immune checkpoint and that blocking VISTA can reprogram suppressive myeloid cells and promote a T cell-stimulatory tumor microenvironment.2 In this study, we further demonstrate that VISTA blockade directly alters the differentiation and the suppressive function of myeloid-derived suppressor cells (MDSC).MethodsFlow cytometry was performed to examine VISTA expression on MDSCs in multiple murine tumor models including the B16BL6 melanoma model, MC38 colon cancer model, and the KPC pancreatic cancer models. To examine the role of VISTA in controlling the differentiation and suppressive function of MDSCs, we cultured wild type (WT) and VISTA.KO bone marrow progenitor cells with GM-CSF and IL-6 to induce BM -derived MDSCs.ResultsOur preliminary results show that VISTA is highly expressed on M-MDSCs in B16BL6, MC38 and KPC tumors. In BM-derived MDSCs, VISTA deletion significantly altered the signaling pathways and the differentiation of MDSCs. Multiple inflammatory signaling pathways were downregulated in VISTA KO MDSCs, resulting in decreased production of cytokines such as IL1 and chemokines such as CCL2/4/9, as well as significantly impaired their ability to suppress the activation of CD8+ T cells. The loss of suppressive function in VISTA KO MDSCs is correlated with significantly reduced expression of iNOS. To validate the results from BM-MDSCs, we sorted CD11b+CD11c-Ly6C+Ly6G- M-MDSCs and CD11b+CD11c-Ly6G+ G-MDSCs from B16BL6 tumor tissues and tested the ability of a VISTA-blocking mAb to reverse the suppressive effects of tumor-derived MDSCs. Our results show that blocking VISTA impaired the suppressive function of tumor-derived M-MDSC but not G-MDSCs.ConclusionsTaken together, these results demonstrate a crucial role of VISTA in regulating the differentiation and function of MDSCs, and that blocking VISTA abolishes MDSC-mediated T cell suppression, thereby boosting.Ethics ApprovalAll in vivo studies were reviewed and approved by Institutional Animal Care and Use Committee (Approval number 2019-2142).ReferencesXu W, Hire T, Malarkannan, S. et al. The structure, expression, and multifaceted role of immune-checkpoint protein VISTA as a critical regulator of anti-tumor immunity, autoimmunity, and inflammation. Cell Mol Immunol 2018;15:438–446.Xu W, Dong J, Zheng Y, et al. Immune-checkpoint protein VISTA regulates antitumor immunity by controlling myeloid cell-mediated inflammation and immunosuppression. Cancer Immunol Res 2019;7:1497–510.

scholarly journals Delicate Role of PD-L1/PD-1 Axis in Blood Vessel Inflammatory Diseases: Current Insight and Future Significance

2020 ◽  
Vol 21 (21) ◽  
pp. 8159
Author(s):  
Priya Veluswamy ◽  
Max Wacker ◽  
Maximilian Scherner ◽  
Jens Wippermann
Keyword(s):  
T Cell ◽  
Blood Vessel ◽  
T Cell Activation ◽  
Immune Checkpoint ◽  
Cell Activation ◽  
Inflammatory Diseases ◽  
Vascular Inflammation ◽  
Experimental Models ◽  
Cell Immunity

Immune checkpoint molecules are the antigen-independent generator of secondary signals that aid in maintaining the homeostasis of the immune system. The programmed death ligand-1 (PD-L1)/PD-1 axis is one among the most extensively studied immune-inhibitory checkpoint molecules, which delivers a negative signal for T cell activation by binding to the PD-1 receptor. The general attributes of PD-L1’s immune-suppressive qualities and novel mechanisms on the barrier functions of vascular endothelium to regulate blood vessel-related inflammatory diseases are concisely reviewed. Though targeting the PD-1/PD-L1 axis has received immense recognition—the Nobel Prize in clinical oncology was awarded in the year 2018 for this discovery—the use of therapeutic modulating strategies for the PD-L1/PD-1 pathway in chronic inflammatory blood vessel diseases is still limited to experimental models. However, studies using clinical specimens that support the role of PD-1 and PD-L1 in patients with underlying atherosclerosis are also detailed. Of note, delicate balances in the expression levels of PD-L1 that are needed to preserve T cell immunity and to curtail acute as well as chronic infections in underlying blood vessel diseases are discussed. A significant link exists between altered lipid and glucose metabolism in different cells and the expression of PD-1/PD-L1 molecules, and its possible implications on vascular inflammation are justified. This review summarizes the most recent insights concerning the role of the PD-L1/PD-1 axis in vascular inflammation and, in addition, provides an overview exploring the novel therapeutic approaches and challenges of manipulating these immune checkpoint proteins, PD-1 and PD-L1, for suppressing blood vessel inflammation.

scholarly journals The role of dendritic cells for therapy of B-cell lymphoma with immune checkpoint inhibitors

2020 ◽  
Author(s):  
Anne Scheuerpflug ◽  
Fatima Ahmetlić ◽  
Vera Bauer ◽  
Tanja Riedel ◽  
Martin Röcken ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
B Cell ◽  
Immune Checkpoint ◽  
Cell Lymphoma ◽  
T Cell Responses ◽  
B Cell Lymphoma ◽  
Cell Responses

Abstract Immune checkpoint blocking (ICB) is a promising new tool of cancer treatment. Yet, the underlying therapeutic mechanisms are not fully understood. Here we investigated the role of dendritic cells (DCs) for the therapeutic effect of ICB in a λ-MYC-transgenic mouse model of endogenously arising B-cell lymphoma. The growth of these tumors can be effectively delayed by antibodies against CTLA-4 and PD-1. Tumor-infiltrating DCs from mice having received therapy showed an upregulation of costimulatory molecules as well as an augmented IL-12/IL-10 ratio as compared to untreated controls. Both alterations seemed to be induced by interferon-γ (IFN-γ), which is upregulated in T cells and natural killer cells upon ICB. Furthermore, the enhanced IL-12/IL-10 ratio, which favors Th1-prone antitumor T-cell responses, was a consequence of direct interaction of ICB antibodies with DCs. Importantly, the capability of tumor-infiltrating DCs of stimulating peptide-specific or allogeneic T-cell responses in vitro was improved when DCs were derived from ICB-treated mice. The data indicate that ICB therapy is not only effective by directly activating T cells, but also by triggering a complex network, in which DCs play a pivotal role at the interface between innate and adaptive antitumor responses.

scholarly journals Inhibiting the Unconventionals: Importance of Immune Checkpoint Receptors in γδ T, MAIT, and NKT Cells

Cancers ◽  
2021 ◽  
Vol 13 (18) ◽  
pp. 4647
Author(s):  
Elisa Catafal-Tardos ◽  
Maria Virginia Baglioni ◽  
Vasileios Bekiaris
Keyword(s):  
T Cells ◽  
T Cell ◽  
Immune Checkpoint ◽  
Immune Surveillance ◽  
Nkt Cells ◽  
T Cell Subsets ◽  
Cancer Models ◽  
Clinical Responses ◽  
Checkpoint Receptors ◽  
Cancer Immunotherapies

In recent years, checkpoint inhibitor (CPI) therapy has shown promising clinical responses across a broad range of cancers. However, many patients remain unresponsive and there is need for improvement. CPI therapy relies on antibody-mediated neutralization of immune inhibitory or checkpoint receptors (ICRs) that constitutively suppress leukocytes. In this regard, the clinical outcome of CPI therapy has primarily been attributed to modulating classical MHC-restricted αβ T cell responses, yet, it will inevitably target most lymphoid (and many myeloid) populations. As such, unconventional non-MHC-restricted gamma delta (γδ) T, mucosal associated invariant T (MAIT) and natural killer T (NKT) cells express ICRs at steady-state and after activation and may thus be affected by CPI therapies. To which extent, however, remains unclear. These unconventional T cells are polyfunctional innate-like lymphocytes that play a key role in tumor immune surveillance and have a plethora of protective and pathogenic immune responses. The robust anti-tumor potential of γδ T, MAIT, and NKT cells has been established in a variety of preclinical cancer models and in clinical reports. In contrast, recent studies have documented a pro-tumor effect of innate-like T cell subsets that secrete pro-inflammatory cytokines. Consequently, understanding the mechanisms that regulate such T cells and their response to CPI is critical in designing effective cancer immunotherapies that favor anti-tumor immunity. In this Review, we will discuss the current understanding regarding the role of immune checkpoint regulation in γδ T, MAIT, and NKT cells and its importance in anti-cancer immunity.

scholarly journals Unveiling a Critical Role of Thrombin in Enhanced CD8+ T Cell Response to Cancer

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4918-4918
Author(s):  
Rachel Cantrell ◽  
Leah A. Rosenfeldt ◽  
Duaa Mureb ◽  
Balkrishan Sharma ◽  
Alexey Revenko ◽  
...  
Keyword(s):  
T Cell ◽  
Tumor Microenvironment ◽  
Cancer Patients ◽  
Immune Checkpoint ◽  
Thrombin Generation ◽  
Critical Role ◽  
Cd8 T Cell ◽  
Checkpoint Inhibition ◽  
Immune Checkpoint Inhibition

A serious and life-threatening cancer-associated sequelae is venous thromboembolism (VTE). Indeed, VTE is the second leading cause of death in cancer patients, second only to the malignancy itself. Cancer patients with VTE or at high risk for VTE are generally treated with anticoagulants, which limit thrombin generation. While it's been widely accepted that thrombin plays a role in cancer progression, the effects thrombin has on other cell types within the tumor microenvironment (TME) have not been thoroughly studied. An understudied role of thrombin may be found in its ability to drive T cell functions. Recently, we have identified thrombin as a potential enhancer of CD8+ T cell effector functions by signaling through the protease activated receptor 1 (PAR-1). Our preliminary data shows that thrombin increases CD8+ T cell survival in a PAR-1 dependent fashion. CD8+ tumor infiltrating lymphocytes (TILs) play a critical role in tumor clearance through their cytolytic and anti-tumor cytokine producing capacity. However, the hostile tumor microenvironment (TME) promotes a gradual reduction in CD8+ TIL capacity to produce cytokines and kill targets. Specific components of the TME, including PDL1 expression, are associated with loss of T cell functionality. A promising strategy to block the interaction of CD8+ TILs and the inhibitory TME components is immune checkpoint inhibition (ICI) therapy, as shown by effective blockade of PD1 signaling by anti-PD1 antibodies. However, these ICI therapies leave many patients unresponsive, highlighting the necessity to uncover additional underlying mechanisms involved in modulating CD8+ T cell responses against cancer. Our preliminary findings lead us to hypothesize that thrombin, in conjunction with PD1 blockade, may work in synergy to promote CD8+ T cell killing of tumors. Consistent with our hypothesis, preliminary results suggest that thrombin is necessary for a robust anti-tumor immune response following ICI in vivo. Here, cohorts of C57BL/6 mice with low or normal circulating prothrombin levels bearing B16 tumors were treated with an anti-PD1 antibody or control IgG. Anti-PD1 therapy significantly limited tumor growth in mice with normal prothrombin levels, but had no impact on tumor growth in mice with low prothrombin levels. A major implication of our findings is that limiting thrombin generation with anticoagulants may be detrimental in the context of immune checkpoint inhibition treatment. Better defining the potential risk of reducing ICI efficacy by concurrent treatment with anticoagulants will require a detailed understanding of the role thrombin plays in cancer immunobiology. Disclosures Revenko: Ionis Pharmaceuticals: Employment. Monia:Ionis Pharmaceuticals: Employment. Palumbo:Ionis Pharmaceuticals: Research Funding.

scholarly journals Making a Cold Tumor Hot: The Role of Vaccines in the Treatment of Glioblastoma

2021 ◽  
Vol 11 ◽  
Author(s):  
Stephen C. Frederico ◽  
John C. Hancock ◽  
Emily E. S. Brettschneider ◽  
Nivedita M. Ratnam ◽  
Mark R. Gilbert ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Immune System ◽  
T Cell ◽  
Immune Checkpoint ◽  
Vaccine Development ◽  
T Cell Responses ◽  
Immune Monitoring ◽  
T Cell Response ◽  
Cell Responses

The use of immunotherapies for the treatment of brain tumors is a topic that has garnered considerable excitement in recent years. Discoveries such as the presence of a glymphatic system and immune surveillance in the central nervous system (CNS) have shattered the theory of immune privilege and opened up the possibility of treating CNS malignancies with immunotherapies. However, despite many immunotherapy clinical trials aimed at treating glioblastoma (GBM), very few have demonstrated a significant survival benefit. Several factors for this have been identified, one of which is that GBMs are immunologically “cold,” implying that the cancer does not induce a strong T cell response. It is postulated that this is why clinical trials using an immune checkpoint inhibitor alone have not demonstrated efficacy. While it is well established that anti-cancer T cell responses can be facilitated by the presentation of tumor-specific antigens to the immune system, treatment-related death of GBM cells and subsequent release of molecules have not been shown to be sufficient to evoke an anti-tumor immune response effective enough to have a significant impact. To overcome this limitation, vaccines can be used to introduce exogenous antigens at higher concentrations to the immune system to induce strong tumor antigen-specific T cell responses. In this review, we will describe vaccination strategies that are under investigation to treat GBM; categorizing them based on their target antigens, form of antigens, vehicles used, and pairing with specific adjuvants. We will review the concept of vaccine therapy in combination with immune checkpoint inhibitors, as it is hypothesized that this approach may be more effective in overcoming the immunosuppressive milieu of GBM. Clinical trial design and the need for incorporating robust immune monitoring into future studies will also be discussed here. We believe that the integration of evolving technologies of vaccine development, delivery, and immune monitoring will further enhance the role of these therapies and will likely remain an important area of investigation for future treatment strategies for GBM patients.

scholarly journals The CC′ loop of IgV domains of the immune checkpoint receptors, plays a key role in receptor:ligand affinity modulation

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Shankar V. Kundapura ◽  
Udupi A. Ramagopal
Keyword(s):  
Immune Checkpoint ◽  
Rational Design ◽  
Protein Docking ◽  
Immune Checkpoints ◽  
Negative Regulators ◽  
Durable Response ◽  
Affinity Modulation ◽  
Polar Interactions ◽  
Checkpoint Receptors

AbstractAntibodies targeting negative regulators of immune checkpoints have shown unprecedented and durable response against variety of malignancies. While the concept of blocking the negative regulators of the immune checkpoints using mAbs appears to be an outstanding approach, their limited effect and several drawbacks, calls for the rational design of next generation of therapeutics. Soluble isoforms of the negative regulators of immune checkpoint pathways are expressed naturally and regulate immune responses. This suggests, affinity-modified versions of these self-molecules could be effective lead molecules for immunotherapy. To obtain better insights on the hotspot regions for modification, we have analysed structures of 18 immune receptor:ligand complexes containing the IgV domain. Interestingly, this analysis reveals that the CC′ loop of IgV domain, a loop which is distinct from CDRs of antibodies, plays a pivotal role in affinity modulation, which was previously not highlighted. It is noteworthy that a ~5-residue long CC′ loop in a ~120 residue protein makes significant number of hydrophobic and polar interactions with its cognate ligand. The post-interaction movement of CC′ loop to accommodate the incoming ligands, seems to provide additional affinity to the interactions. In silico replacement of the CC′ loop of TIGIT with that of Nectin-2 and PVR followed by protein docking trials suggests a key role of the CC′ loop in affinity modulation in the TIGIT/Nectin pathway. The CC′ loop appears to be a hotspot for the affinity modification without affecting the specificity to their cognate receptors.

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