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区含免疫球蛋白的T细胞活化抑制因子）可以消除大， 对PD-1/CTLA-4阻断具有抗性的已建立肿瘤（“检查点抗性”肿瘤）。我们建议 是因为抗VISTA可以缓解T细胞抑制，也可以减少骨髓来源的抑制细胞， 在肿瘤微环境（TME）中，MDSC的组成和功能。据我们所知， 导致这种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VISTA的高水平表达与较差的存活率相关。本提案的使命是 定义抗VISTA促存活作用在已建立肿瘤中的潜在机制。新兴 认识到VISTA在功能上是双向的，既作为配体又作为受体，并且在细胞上表达， 多个造血谱系（T细胞，骨髓）开辟了一个扩大的机制，可以 解释其在T细胞抑制和MDSC功能中的作用。我们介绍了另一个IG超基因家族VSIG 8 被我们鉴定为VISTA反受体的成员。具体目标1测试了两个假设， VISTA介导的抑制。首先，VISTA作为在APC/MDSC上表达的配体， 通过VSIG 8抑制T细胞。第二，VISTA在T细胞上表达，充当受体，当 VSIG 8激活T细胞抑制。这是两个不同的假设，可以解释 癌症中VISTA介导的免疫抑制他们的决议将带来决定性的新信息， 肿瘤免疫治疗中抗VISTA作用的机制。具体目标#2解决了另一个新的 VISTA作为控制MDSC功能的受体的基本作用。我们报告说，VISTA瞄准结果 TME内Ly 6 G + MDSC和肿瘤相关巨噬细胞（TAM）的显著减少。 其他研究证实了VISTA在控制MDSC生物学方面的核心和深刻的免疫调节作用 （介体产生、趋化性等）。我们提出VISTA靶向的多效性效应是由于VISTA的靶向效应导致的。 MDSC影响TME的免疫状态，对消除“检查点耐药”至关重要。 肿瘤的所有鼠研究均支持TME内VISTA表达升高将导致TME内VISTA表达增加的假设。 损害肿瘤免疫的发展。大肠癌中VISTA mRNA表达的研究 患者揭示了TME中VISTA表达升高与TME中总体较短时间之间的强相关性。 生存这种相关性是由粒细胞和单核细胞浸润驱动的。具体目标#3 我们建议通过以下方法大大提高我们对人类和小鼠结直肠癌中VISTA表达的分辨率： 结合遗传学和成像技术来确定TME中VISTA的空间分布， 详细描述VISTA对TME白细胞亚群的强度和分布。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的临床开发 2016年1月进入临床的治疗方法。