Overcoming the immune evasion mechanism of Merkel cell polyomavirus-associated Merkel cell carcinoma

克服默克尔细胞多瘤病毒相关默克尔细胞癌的免疫逃避机制

• 批准号: 9894065
• 负责人: Jianxin You
• 金额: $ 26.05万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-03-01 至 2022-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9894065
• 关键词: Agonist; Antibody Therapy; Biological Assay; Biological Response Modifiers; CD8-Positive T-Lymphocytes; Cell Death; Cell physiology; Cells; Clinical; Complement; DNA; DNA Damage; Data; Dependovirus; Dimethylxanthenone Acetic Acid; Effectiveness; Engineering; Gene Activation; Gene Expression; Gene Silencing; Genome; Goals; Grant; Human; Human Engineering; Immune; Immune Evasion; Immune checkpoint inhibitor; Immunity; Immunocompromised Host; Immunologic Surveillance; Immunologics; Immunosuppression; In Vitro; Infiltration; Light; Malignant Epithelial Cell; Malignant Neoplasms; Mediating; Merkel Cells; Merkel cell carcinoma; Methods; Modeling; Mus; Nature; Neoplasm Metastasis; Oncoproteins; PD-1 blockade; PD-1/PD-L1; Patients; Polyomavirus; Production; Repression; Research Proposals; Resistance; Risk; Risk Factors; Signal Transduction; Skin; Skin Cancer; Stimulator of Interferon Genes; T cell response; T-Cell Activation; T-Lymphocyte; Testing; Therapeutic; Therapeutic Agents; Toxic effect; Treatment Efficacy; Tumor Antigens; Tumor Escape; Tumor-infiltrating immune cells; Viral Oncogene; Xenograft Model; adeno-associated viral vector; anti-PD1 antibodies; anti-tumor immune response; base; cancer cell; cancer genome; cancer immunotherapy; cell injury; cell killing; cell motility; checkpoint therapy; clinical translation; cytokine; cytotoxicity; effective therapy; engineered T cells; gene function; humanized mouse; immune checkpoint; immune checkpoint blockade; immune function; immune resistance; improved; in vivo; mouse model; multidisciplinary; mutant; neoplastic cell; novel; novel strategies; novel therapeutics; response; tool; tumor; tumorigenic

Project Summary Tumor immune escape represents a major obstacle in cancer immunotherapy, however, the underlying mechanism remains poorly understood. The goal of this exploratory research proposal is to overcome the immune evasion mechanism of Merkel cell carcinoma (MCC), a highly lethal skin cancer associated with merkel cell polyomavirus (MCPyV). Currently, there is no effective therapeutic treatment for metastatic MCCs. A large portion of MCCs is resistant to the immune checkpoint therapies. Immuno-suppression is an important risk factor for MCPyV- associated MCC. Furthermore, in more than 90% of MCC patients with normal immune function, MCC tumors continue to develop despite the production of T cells recognizing MCPyV-encoded oncoproteins expressed in the tumors. Tumor-infiltrating MCPyV-specific T cells are critical for improved patient survival, and yet they are sparsely present in a very small percentage of MCCs and show significantly reduced activation. These observations support that MCPyV-associated MCCs may escape immunological destruction by restricting T-cell intratumoral infiltration and repressing T cell activation. However, the underlying mechanisms are largely unknown. We recently discovered that Stimulator of Interferon Genes (STING) is completely silenced in MCPyV+ MCCs. Because STING function is critical for sensing damaged DNA in cancer cells to stimulate cytokine production, intratumoral CD8+ T cell infiltration, and antitumor T cell responses, we hypothesize that STING silencing in MCC contributes to its immune suppressive nature and that reactivation of STING in MCCs can stimulate T cell infiltration and antitumor cytotoxicity. To test this hypothesis, we have developed a novel approach to specifically activate STING in MCC but not other human cells. This approach will be combined with engineered human T cells, an MCC mouse xenograft model, as well as a humanized mouse tumor model to define the functional impact of STING reactivation on stimulating T cell intratumoral infiltration and antitumor immune responses. Because STING signaling is also important for enhancing the antitumor efficacy of checkpoint inhibitors, we will combine our new STING-reactivating method with PD-1 blockade to achieve synergistic antitumor activity and circumvent MCC resistance to immune checkpoint therapies. These studies have the potential to overcome the MCC immunoescape mechanism and develop novel therapeutic strategies to treat the highly aggressive MCC cancers. Our study may also reveal a novel strategy for overcoming the toxicity and limitation of traditional human STING agonist-based therapies.

项目摘要 肿瘤免疫逃生是癌症免疫疗法的主要障碍 潜在的机制仍然知之甚少。这项探索性研究的目标 提案是要克服默克尔细胞癌（MCC）的免疫逃避机制，A 与默克尔细胞多瘤病毒（MCPYV）相关的高度致命的皮肤癌。目前，有 没有有效的转移性MCC治疗治疗。大部分MCC对 免疫检查点疗法。免疫抑制是MCPYV-的重要危险因素 相关的MCC。此外，超过90％的MCC免疫功能正常患者 尽管产生了识别MCPYV编码的T细胞，但MCC肿瘤仍在继续发展 肿瘤蛋白在肿瘤中表达。肿瘤浸润的MCPYV特异性T细胞对于 改善了患者的生存，但它们稀疏地存在于很小的MCC中 并显示出显着降低的激活。这些观察结果支持MCPYV相关 MCC可以通过限制T细胞肿瘤内浸润和 抑制T细胞激活。但是，基本机制在很大程度上是未知的。我们 最近发现，干扰素基因（STING）的刺激器完全沉默 MCPYV+ MCC。因为刺激功能对于将癌细胞中受损受损的DNA感知到 刺激细胞因子的产生，肿瘤内CD8+ T细胞浸润和抗肿瘤T细胞 回答，我们假设MCC中的刺痛沉默有助于其免疫抑制 自然和MCC中刺的重新激活可以刺激T细胞浸润和抗肿瘤 细胞毒性。为了检验这一假设，我们开发了一种新颖的方法来专门激活 在MCC中刺，但没有其他人类细胞。这种方法将与工程结合 人类T细胞，一种MCC小鼠异种移植模型，以及人源化的小鼠肿瘤模型 定义刺激重新激活对刺激T细胞内肿瘤内浸润的功能影响 和抗肿瘤免疫反应。因为刺激信号对于增强 检查点抑制剂的抗肿瘤功效，我们将结合我们的新刺激方法 使用PD-1阻断以实现协同的抗肿瘤活性，并避免MCC抗性 免疫检查点疗法。这些研究有可能克服MCC 免疫扫描机制并制定新颖的治疗策略来治疗高度 激进的MCC癌症。我们的研究还可能揭示了一种克服的新策略 传统人类刺痛激动剂疗法的毒性和局限性。