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(含V区免疫球蛋白的T细胞激活抑制因子)可以根除大、 对PD-1/CTLA-4阻断有抵抗力的已建立的肿瘤(“关卡抵抗型”肿瘤)。我们建议这样做 是因为抗Vista可以缓解T细胞抑制，并减少髓系来源的抑制细胞 (MDSC)肿瘤微环境(TME)的组成和功能。据我们所知，没有 导致这一结果的其他基于抗体的治疗。此外，人类肿瘤的数据显示， TME中高水平的VistA表达与较差的存活率相关。这项提议的使命是 确定在已建立的肿瘤中潜在的抗Vista促进生存的影响的机制。新兴市场 认识到Vista在功能上是双向的，既是配体又是受体，表达于 多个造血系(T细胞，髓系)开辟了广泛的机制，可以 说明其在T细胞抑制和MDSC功能中的作用。我们介绍了VSIG8，另一个免疫球蛋白超基因家族 我们鉴定为Vista反受体的成员。特定目标#1测试了两个解释以下假设的假设 Vista介导的压制。首先，Vista作为APC/MDSCs上表达的配体，触发 VSIG8对T细胞的抑制作用第二，Vista在T细胞上表达，作为受体，当 被VSIG8激活会触发T细胞抑制。这是两个截然不同的假设，可以解释 Vista介导的癌症免疫抑制。他们的决议将带来有关 抗Vista在肿瘤免疫治疗中的作用机制。第二个具体目标是解决另一个新问题 Vista作为控制MDSC功能的受体的基础作用。我们报告Vista目标结果 在TME内Ly6G+MDSCs和肿瘤相关巨噬细胞(TAMs)显著减少。 更多研究证实Vista在控制MDSC生物学中发挥着核心而深刻的免疫调节作用 (介体产生、趋化性等)。我们认为，Vista靶向的多效性效应 MDSCs影响TME的免疫状态，是消除“检查点抵抗”的关键。 肿瘤。所有的小鼠研究都支持这样的假设，即TME中VistA的高表达将 损害肿瘤免疫功能的发展。VistA基因在结直肠癌组织中的表达 患者显示TME中Vista的高表达与整体较短有很强的相关性 生死存亡。这种相关性是由粒细胞和单核细胞的渗透所驱动的。在具体目标#3中，我们 建议通过以下方式大幅提高VistA在人和小鼠结直肠癌中的表达分辨率 结合遗传和成像技术确定Vista在TME中的空间分布并定义 详细分析了VistA在TME白细胞亚群上的表达强度和分布。我们建议这些策略 将提供明确和决定性的预测生物标志物，并指导抗Vista的临床发展 2016年1月进入诊所的疗法。