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 细胞激活抑制剂）可以根除大的、 已确定对 PD-1/CTLA-4 阻断具有抗性的肿瘤（“检查点抗性”肿瘤）。我们提议这个 是因为抗VISTA可以解除T细胞抑制，同时也减少骨髓源性抑制细胞 (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，人类肿瘤的数据表明 TME 中高水平的 VISTA 表达与较差的生存率相关。该提案的使命是 定义抗 VISTA 对已形成肿瘤的促生存影响的机制。新兴的 认识到 VISTA 在功能上是双向的，既充当配体又充当受体，并在 多种造血谱系（T 细胞、骨髓细胞）开辟了更广泛的机制， 解释其在 T 细胞抑制和 MDSC 功能中的作用。我们推出另一个 Ig 超基因家族 VSIG8 我们确定为 VISTA 反受体的成员。具体目标#1 测试两个假设，解释 VISTA 介导的抑制。首先，VISTA 作为 APC/MDSC 上表达的配体，触发 通过 VSIG8 抑制 T 细胞。其次，VISTA 在 T 细胞上表达，充当受体，当 VSIG8 参与会触发 T 细胞抑制。这是两个不同的假设，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 解决了另一个新问题 VISTA 作为控制 MDSC 功能的受体的基本作用。我们报告 VISTA 定位结果 TME 内 Ly6G+ MDSC 和肿瘤相关巨噬细胞 (TAM) 显着减少。 其他研究证实 VISTA 在控制 MDSC 生物学方面具有重要而深远的免疫调节作用 （介体产生、趋化性等）。我们认为 VISTA 靶向的多效性效应 MDSC 影响 TME 的免疫状态，对于消除“检查点抵抗”至关重要 肿瘤。所有小鼠研究都支持这样的假设：TME 内 VISTA 表达的增加将 损害肿瘤免疫的发展。结直肠癌中VISTA mRNA表达的评价 患者显示 TME 中 VISTA 表达升高与整体较短之间存在很强的相关性 生存。这种相关性是由粒细胞和单核细胞浸润驱动的。在具体目标#3中，我们 建议通过以下方法大大提高人类和小鼠结直肠癌中 VISTA 表达的分辨率 结合遗传和成像技术来定义 VISTA 在 TME 中的空间分布，并定义 详细显示 VISTA 对 TME 白细胞亚群的强度和分布。我们建议这些策略 将提供明确且决定性的预测生物标志物并指导抗VISTA的临床开发 2016 年 1 月进入临床的疗法。