VISTA, a novel checkpoint that suppresses anti-tumor T cell responses

描述(由申请人提供)：保护性抗肿瘤免疫因免疫抑制机制而受损。免疫检查点蛋白，包括CTLA-4、PD-1和B7-H4，作为“效应分子”发挥作用，使T细胞对癌症的反应失效。虽然使用单抗的检查点阻断在临床试验中显示了积极的结果，但令人失望的是，总体应答率低至6-21%。因此，鉴定新的检查点蛋白是非常必要的。我们发现了一种新的免疫球蛋白超家族抑制配体，命名为V域免疫球蛋白T细胞激活抑制因子(VistA)。我们假设Vista作为控制抗肿瘤免疫的额外的和关键的免疫检查点配体发挥作用。这项拨款提案的目标是确定Vista介导的免疫抑制的分子和细胞机制，既通过它对T效应细胞激活的直接作用，也通过它对其他免疫抑制细胞类型的调节功能，后者反过来控制T效应细胞对癌症的反应。因此，具体目标是：(1)确定Vista抑制T细胞激活的分子机制，以及它如何与另一条免疫检查点途径PD-L1/PD-1合作来抑制肿瘤特异性T细胞反应。(2)探讨Vista在Foxp3+CD4+Tregs发育和功能中的作用。(3)明确Vista在正常生理状态和肿瘤发生过程中对单核巨噬细胞的发育、分化和功能的影响。包括Vista单抗、VISTAKO小鼠和Vista条件性KO小鼠在内的一系列新试剂和模型将用于本研究。除了可移植的黑色素瘤B16F10模型外，我们还将使用临床相关的诱导黑色素瘤模型进行机制研究和评估基于Vista的治疗策略。影响：任何成功的癌症免疫治疗策略都必须考虑负面免疫调节剂，以阻止最佳抗肿瘤免疫的发展。作为一种新的免疫检查点途径，VistA为肿瘤的免疫干预提供了新的靶点。这项研究将提供关于Vista在肿瘤发生过程中介导的免疫调节的答案。它将建立一种新的范式，其中Vista和PD-L1/PD1协同控制T细胞反应，从而为单独或与其他免疫检查点途径联合靶向Vista用于癌症免疫治疗提供了理论基础。此外，这项研究将建立一个关于肿瘤如何利用Vista来改变Treg和单核细胞的分化和功能的新范式，从而为在癌症免疫治疗中靶向这些重要的免疫抑制因子提供新的策略。

DESCRIPTION (provided by applicant): Protective anti-tumor immunity is impaired by immunosuppressive mechanisms. Immune checkpoint proteins, including CTLA-4, PD-1, and B7-H4, function as "effector molecules" to disable T-cell responses against cancer. Although checkpoint blockade using monoclonal antibodies (mab) have shown positive outcomes in clinical trials, the overall response rate has been disappointingly as low as 6-21%. Therefore, identifying novel checkpoint proteins is critically needed. We have discovered and functionally characterized a new Ig-superfamily inhibitory ligand, designated V-domain Immunoglobulin Suppressor of T cell Activation (VISTA). We hypothesize that VISTA functions as an additional and crucial immune-checkpoint ligand that controls anti-tumor immunity. The goal in this grant proposal is to determine the molecular and cellular mechanisms of VISTA-mediated immune suppression, both via its direct effect on T effector cell activation, and via its regulatory functon on other immunosuppressive cell types, which in turn control T effector cell responses against cancer. Accordingly, the specific Aims are: (1) Determine the molecular mechanisms whereby VISTA suppresses T-cell activation, and how it collaborates with another immune-checkpoint pathway PD-L1/PD-1 to suppress tumor-specific T-cell responses. (2) Determine the role of VISTA on the development and function of Foxp3+CD4+ Tregs. (3) Define the role of VISTA on the development, differentiation, and function of mononuclear phagocytes in the normal physiological state and during tumorigenesis. A collection of novel reagents and models including VISTA mab, VISTAKO mice, and VISTA conditional KO mice will be used for this study. In addition to a transplantable melanoma B16F10 model, we will employ a clinically relevant inducible-melanoma model for mechanistic studies and assessing VISTA-based therapeutic strategies. Impact: Any successful cancer immunotherapeutic strategy must consider the negative immune regulators that prevent the development of optimal anti-tumor immunity. As a novel immune checkpoint pathway, VISTA provides a new target for the immune intervention in cancer. This study will provide answers regarding VISTA- mediated immune regulation during tumorigenesis. It will establish a novel paradigm in which VISTA and PD- L1/PD1 synergize to control T-cell responses, thus providing a rationale for targeting VISTA either alone or in combination with other immune checkpoint pathways for cancer immunotherapy. Further, this study will establish a new paradigm regarding how tumors utilize VISTA to alter the differentiation and functions of Tregs and monocytes, thus providing novel strategies for targeting these prominent immune-suppressors in cancer immunotherapy.