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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要肿瘤免疫逃逸是癌症免疫治疗的一个主要障碍，然而，其根本机制仍知之甚少。本次探索性研究的目标该提案旨在克服默克尔细胞癌（MCC）的免疫逃避机制，这是一种与默克尔细胞多瘤病毒（MCPyV）相关的高致死性皮肤癌。目前，有对于转移性 MCC 尚无有效的治疗方法。大部分 MCC 具有抵抗力免疫检查点疗法。免疫抑制是 MCPyV- 的重要危险因素关联的中冶集团。此外，在90%以上免疫功能正常的MCC患者中，尽管产生了识别 MCPyV 编码的 T 细胞，MCC 肿瘤仍在继续发展肿瘤中表达的癌蛋白。肿瘤浸润 MCPyV 特异性 T 细胞对于改善了患者的生存率，但它们很少出现在极小比例的 MCC 中并显示激活显着减少。这些观察结果支持 MCPyV 相关 MCC 可能通过限制 T 细胞瘤内浸润来逃避免疫破坏抑制 T 细胞活化。然而，其根本机制在很大程度上尚不清楚。我们最近发现干扰素基因刺激物（STING）在 MCPyV+ MCC。因为 STING 功能对于感知癌细胞中受损的 DNA 至关重要刺激细胞因子产生、瘤内 CD8+ T 细胞浸润和抗肿瘤 T 细胞反应，我们假设 MCC 中的 STING 沉默有助于其免疫抑制 MCC 中 STING 的重新激活可以刺激 T 细胞浸润和抗肿瘤细胞毒性。为了检验这个假设，我们开发了一种新方法来专门激活 STING 存在于 MCC 中，但不存在于其他人类细胞中。该方法将与工程化相结合人类 T 细胞、MCC 小鼠异种移植模型以及人源化小鼠肿瘤模型定义 STING 重新激活对刺激 T 细胞瘤内浸润的功能影响和抗肿瘤免疫反应。因为 STING 信号对于增强检查点抑制剂的抗肿瘤功效，我们将结合我们新的 STING 重新激活方法与 PD-1 阻断实现协同抗肿瘤活性并规避 MCC 耐药性免疫检查点疗法。这些研究有可能克服 MCC 免疫逃逸机制并开发新的治疗策略来治疗高度侵袭性 MCC 癌症。我们的研究还可能揭示一种克服这一问题的新策略传统人类 STING 激动剂疗法的毒性和局限性。