Saturday, May 17, 2025
5/17/2025
Identifying the Mechanism of Resistance to Immunotherapy in Merkel Cell Carcinoma (for Zachary Reinstein) - Project Summary/Abstract Merkel cell carcinoma (MCC) is the most aggressive and fatal cancer on a case-by-case basis with rapidly rising incidence. Approximately 80% of MCC cases are caused by Merkel cell polyomavirus, which expresses two viral oncogenes known as large T antigen and small T antigen that are required for clonal carcinogenesis. Notably, although MCC is highly aggressive, approximately 50% of patients treated with immune checkpoint blockade (ICB) respond to treatment. With approximately equal numbers of responsive patients to resistant patients and small, shared neoantigen repertoire, virus positive (VP) MCC serves as a model of T cell response in cancer. It is unknown why some patients respond to ICB while others resist treatment. A critical unmet need is to develop treatments for patients with primary or acquired resistant to ICB. To elucidate this mechanism and identify biomarkers of ICB response, we have collected the largest clinically annotated database of primary MCC samples treated with ICB. We have identified a subset of T cells that drive ICB response. In this project, we will elucidate the mechanism by which these cells mediate response to ICB. We will spatially and functionally identify which receptor-ligand interactions are most critical in triggering a response by these T cells. Next, we will identify specific T cell receptors that recognize tumor antigens. Finally, we will characterize anti-MCC T cells in the tumor microenvironment that are causing this response. These results will validate the prognostic potential of these cells and identify the mechanism by which it drives ICB response in VP MCC. My overall career goal is to become a successful, independent physician-scientist. The rigorous training plan proposed in this fellowship will allow me to achieve that goal by gaining research skills and knowledge in cellular immunology and bioinformatics. I will be mentored by Dr. Jaehyuk Choi, an expert physician-scientist in MCC, who has devised a training plan to develop all necessary research skills, communication skills and promote my professional development. This fellowship will broaden our understanding of MCC immunology and identify potential novel therapeutic strategies, as well as provide the necessary foundation for my future career as a physician-scientist.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).