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

VISTA，一种抑制抗肿瘤 T 细胞反应的新型检查点

• 批准号: 9096775
• 负责人: Li Lily Wang
• 金额: $ 1.56万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-01 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9096775
• 关键词: Address; Antibodies; Applications Grants; Biological Response Modifiers; Cells; Clinical Trials; Collection; Cytotoxic T-Lymphocyte-Associated Protein 4; Data; Defect; Development; Effector Cell; Foundations; Frequencies; Generations; Genetic; Goals; Homeostasis; Human; IL2RA gene; Immune; Immune Targeting; Immune response; Immunity; Immunoglobulin Domain; Immunosuppression; Immunosuppressive Agents; Immunotherapeutic agent; In Vitro; Inflammation; Inflammatory; Intervention; Knockout Mice; Lead; Leukocytes; Ligands; Malignant Neoplasms; Maps; Mediating; Modeling; Molecular; Molecular Target; Monoclonal Antibodies; Mononuclear; Mus; Myelogenous; Myeloid Cells; Myelopoiesis; Outcome; PDCD1LG1 gene; Pathway interactions; Phagocytes; Phenotype; Physiological; Play; Proteins; Reagent; Regulation; Regulatory T-Lymphocyte; Role; Signal Transduction; Suppressor-Effector T-Lymphocytes; T cell response; T-Cell Activation; T-Lymphocyte; Therapeutic; Therapeutic Effect; Tumor Immunity; Ursidae Family; VTCN1 gene; base; cancer immunotherapy; cell type; clinically relevant; design; melanoma; monocyte; novel; novel strategies; peripheral tolerance; prevent; receptor; response; targeted treatment; tool; tumor; tumor growth; tumor microenvironment; tumorigenesis

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.

描述（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。尽管使用单克隆抗体（mab）的检查点阻断在临床试验中显示出积极的结果，但令人失望的是，总体缓解率低至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igg超家族抑制配体，命名为v域T细胞活化免疫球蛋白抑制因子（VISTA）。我们假设VISTA作为一个额外的和关键的免疫检查点配体，控制抗肿瘤免疫。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，通过其对T效应细胞激活的直接作用，以及通过其对其他免疫抑制细胞类型的调节功能，从而控制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细胞活化的分子机制，以及它如何与另一种免疫检查点途径PD-L1/PD-1协同抑制肿瘤特异性t细胞反应。(2)确定VISTA对Foxp3+CD4+ Tregs的发育和功能的影响。(3)明确VISTA在正常生理状态和肿瘤发生过程中对单核吞噬细胞的发育、分化和功能的作用。本研究将使用一系列新型试剂和模型，包括VISTA单抗、VISTA小鼠和VISTA条件型KO小鼠。除了可移植黑色素瘤B16F10模型外，我们还将采用临床相关的可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阻止最佳抗肿瘤免疫发展的负性免疫调节因子。VISTA作为一种新的免疫检查点通路，为肿瘤的免疫干预提供了新的靶点。这项研究将为肿瘤发生过程中VISTA介导的免疫调节提供答案。它将建立一个新的范例，其中VISTA和PD- L1/PD1协同控制t细胞反应，从而为单独靶向VISTA或与其他免疫检查点途径联合用于癌症免疫治疗提供理论依据。此外，本研究将为肿瘤如何利用VISTA改变treg和单核细胞的分化和功能建立一个新的范式，从而为癌症免疫治疗中针对这些突出的免疫抑制因子提供新的策略。