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 肿瘤免疫逃逸代表了癌症免疫治疗中的主要障碍，然而， 根本的机制仍然知之甚少。这项探索性研究的目标是 一项旨在克服默克尔细胞癌（MCC）免疫逃避机制的提案， 与默克尔细胞多瘤病毒（MCPyV）相关的高致死性皮肤癌。目前还 对于转移性MCC没有有效的治疗方法。很大一部分MCC对 免疫检查点疗法免疫抑制是MCPyV的重要风险因素- 相关MCC此外，在90%以上免疫功能正常的MCC患者中， MCC肿瘤继续发展，尽管产生识别MCPyV编码的T细胞， 肿瘤中表达的癌蛋白。肿瘤浸润性MCPyV特异性T细胞对于免疫调节至关重要。 改善患者生存率，但它们在MCC中的比例非常小 并显示出显著降低的活化。这些观察结果支持MCPyV相关的 MCCs可能通过限制T细胞瘤内浸润而逃避免疫破坏， 抑制T细胞活化。然而，其潜在的机制在很大程度上是未知的。我们 最近发现，干扰素基因刺激因子（STING）是完全沉默的， MCPyV+ MCC。由于STING功能对于检测癌细胞中受损的DNA至关重要， 刺激细胞因子产生、肿瘤内CD 8 + T细胞浸润和抗肿瘤T细胞 因此，我们假设MCC中的STING沉默有助于其免疫抑制反应， STING在MCC中的再活化可以刺激T细胞浸润和抗肿瘤作用。 细胞毒为了验证这一假设，我们开发了一种新的方法， STING在MCC中，而不是其他人类细胞。这种方法将与工程相结合， 人T细胞、MCC小鼠异种移植物模型以及人源化小鼠肿瘤模型， 确定STING再活化对刺激T细胞肿瘤内浸润的功能影响 和抗肿瘤免疫应答。因为STING信号传导对于增强 我们将联合收割机结合我们新的STING-重新激活方法， 与PD-1阻断剂联合使用，以实现协同抗肿瘤活性，并避免MCC对 免疫检查点疗法。这些研究有可能克服MCC 免疫逃逸机制和开发新的治疗策略，以治疗高度 侵袭性MCC癌症。我们的研究还可能揭示一种克服这些障碍的新策略。 传统的基于人STING激动剂的疗法的毒性和局限性。