Targeting VISTA eradicates large, established PD-1/CTLA-4 resistant tumors

靶向 VISTA 根除大型、已确定的 PD-1/CTLA-4 耐药肿瘤

• 批准号: 9917740
• 负责人: RANDOLPH J. NOELLE
• 金额: $ 57万
• 依托单位: DARTMOUTH COLLEGE
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-05-01 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9917740
• 关键词: Ablation; Accounting; Address; Algorithms; Antibodies; Antibody Therapy; Bioinformatics; Bone Marrow; CTLA4 blockade; CTLA4 gene; Cell Culture Techniques; Cell physiology; Cells; Cellular biology; Chemotaxis; Clinic; Clinical; Clinical Trials; Colon Carcinoma; Colorectal Cancer; Combined Modality Therapy; Correlative Study; Data; Development; Elements; Evaluation; Family; Family member; Future; Gene Expression Profiling; Genetic; Genomics; Hematopoietic; Hematopoietic Neoplasms; Human; Image Analysis; Imaging technology; Immune; Immune Targeting; Immune response; Immune system; Immunity; Immunoglobulins; Immunosuppression; Immunotherapeutic agent; Impairment; Infiltration; Investigation; Knock-in Mouse; Knockout Mice; Knowledge; Leukocytes; Ligands; Malignant Neoplasms; Mediating; Mediator of activation protein; Mission; Modeling; Mus; Myelogenous; Myeloid Cells; Myeloid-derived suppressor cells; Myeloproliferative disease; Neoplasm Metastasis; Oncology; Outcome; PD-1 blockade; Pathway interactions; Phase; Production; Proteins; Reporting; Resistance; Resolution; Role; Spatial Distribution; Suppressor-Effector T-Lymphocytes; System; T-Cell Activation; T-Lymphocyte; Testing; Therapeutic; Time; Tumor Immunity; Tumor Suppression; Tumor-associated macrophages; Up-Regulation; base; chemokine; clinical development; cohort; colon cancer patients; conditional knockout; cytokine; design; genetic technology; granulocyte; human disease; immune checkpoint; immune function; immunological status; immunoregulation; improved; in vivo; mRNA Expression; member; monocyte; mouse model; multiplexed imaging; neoplasm immunotherapy; neoplastic cell; novel; patient stratification; pleiotropism; predictive marker; prevent; programmed cell death protein 1; protein expression; receptor; sound; targeted treatment; transcriptome sequencing; tumor; tumor growth; tumor microenvironment

Targeting VISTA (V-region Immunoglobulin-containing Suppressor of T cell Activation) can eradicate large, established tumors that are resistant to PD-1/CTLA-4 blockade (“checkpoint-resistant” tumors). We propose this is because anti-VISTA can relieve T cell suppression and also reduce the myeloid-derived suppressor cell (MDSC) composition and function within the tumor microenvironment (TME). To our knowledge, there is no other antibody-based therapy that results in this outcome. Furthermore, data in human tumors are showing that high levels of VISTA expression in the TME is correlated with poor survival. The mission of this proposal is to define the mechanisms underlying the anti-VISTA pro-survival impact in established tumors. The emerging recognition that VISTA is functionally bi-directional, acting as both a ligand and a receptor and is expressed on multiple hematopoietic lineages (T cells, myeloid) opens up an expanding breadth of mechanisms that could account for its role in T cell suppression and MDSC function. We present VSIG8, another Ig supergene family member that we identified as the VISTA counter-receptor. Specific Aim #1 tests two hypotheses that explain VISTA-mediated suppression. First, that VISTA, acting as a ligand expressed on APCs/MDSCs, triggers suppression of T cells through VSIG8. Second, VISTA expressed on T cells, acting as a receptor, when engaged by VSIG8 triggers T cell suppression. These are two distinct hypotheses that could account for the VISTA-mediated immune suppression in cancer. Their resolution will bring decisive new information on the mechanisms of anti-VISTA action in tumor immunotherapy. Specific Aim #2 addresses yet another new fundamental role of VISTA as a receptor that controls MDSC function. We report that VISTA targeting results in a striking reduction of Ly6G+ MDSCs and tumor associated macrophages (TAMs) within the TME. Additional studies confirm a central and profound immunoregulatory role of VISTA in controlling MDSC biology (mediator production, chemotaxis, etc). We propose that the the pleiotropic effects of VISTA targeting of MDSCs impacts the immune status of the TME and is central to the elimination of “checkpoint-resistant” tumors. All murine studies support the hypothesis that heightened VISTA expression within the TME will impair the development of tumor immunity. The evaluation of mRNA expression of VISTA in colorectal cancer patients revealed a strong correlation between heightened VISTA expression in the TME and shorter overall survival. This correlation was driven by granulocytic and monocytic cell infiltration. In Specific Aim #3 we propose to greatly improve our resolution of VISTA expression in human and mouse colorectal cancer by combined genetic and imaging technologies to define the spatial distribution of VISTA in the TME and define in detail the intensity and distribution of VISTA on TME leukocyte subsets. We propose that these strategies will provide clear and decisive predictive biomarkers and guide the clinical development of anti-VISTA therapies that entered the clinic in January of 2016.

靶向Vista（V-区域免疫球蛋白的T细胞激活抑制剂）可以放射较大， 对PD-1/CTLA-4封锁（“耐检查点”肿瘤）具有抗性的肿瘤。我们提出了这个 是因为抗Vista可以挽救T细胞抑制，也可以减少髓样衍生的抑制细胞 （MDSC）肿瘤微环境（TME）内的组成和功能。据我们所知，没有 其他基于抗体的疗法会导致这种结果。此外，人类肿瘤中的数据表明 TME中高水平的远景表达与存活不良相关。该提议的使命是 定义在已建立的肿瘤中抗杀菌促生物影响的基础机制。新兴 认识到Vista在功能上是双向的，既充当配体和接收器，并且在 多种造血谱系（T细胞，髓样）开辟了一个不断扩展的机制 解释其在T细胞抑制和MDSC功能中的作用。我们提出了另一个IG超值家族VSIG8 我们确定为Vista反受体的成员。特定目标＃1检验了两个解释的假设 远景介导的抑制。首先，那个远景，用作APC/MDSC的配体，触发器 通过VSIG8抑制T细胞。其次，Vista在T细胞上表达，充当接收器，当 由VSIG8参与触发T细胞抑制。这是两个不同的假设，可以说明 远景介导的癌症的免疫抑制。他们的解决方案将带来有关的决定性的新信息 肿瘤免疫疗法中抗Vista作用的机制。特定的目标＃2地址又一个新的 Vista作为控制MDSC功能的接收器的基本作用。我们报告远景目标结果 在TME内的LY6G+ MDSC和肿瘤相关巨噬细胞（TAM）的显着降低中。 其他研究证实了Vista在控制MDSC生物学中的中心和深刻的免疫调节作用 （介体产生，趋化性等）。我们建议远景靶向的多效性 MDSC会影响TME的免疫状态，并且是消除“抗检查点”的核心 肿瘤。所有鼠研究都支持以下假设 损害肿瘤免疫的发展。评估大肠癌中远景的mRNA表达 患者发现TME中的Vista表达增强与整体较短之间存在很强的相关性 生存。该相关性是由粒细胞和单核细胞浸润驱动的。在特定的目标＃3中我们 提议通过 结合遗传和成像技术来定义TME中远景的空间分布并定义 详细说明TME白细胞子集的远景强度和分布。我们建议这些策略 将提供清晰而决定性的预测生物标志物，并指导反武物的临床发展 2016年1月进入诊所的疗法。