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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.

项目总结