Targeting Senescence- and Fibrosis-Associated Tumor States via Engineered Immunity - PROJECT SUMMARY/ABSTRACT CANDIDATE: As a postdoctoral fellow in Dr. Scott Lowe’s lab at Memorial Sloan Kettering Cancer Center (MSKCC), my research has focused on the impact of aberrant cell surface remodeling on CAR T cell therapy and immune evasion. My long-term goal is to establish an independent research program aimed at discovering new cancer cell-specific surface antigens for cell therapy and understanding mechanisms of resistance to immunotherapy. The proposed research will lay a solid foundation for establishing my own research group by the end of the mentored phase of this award. To ensure my successful transition to independence, I have developed a detailed training plan focusing on four key areas: (1) scientific and career mentorship; (2) expansion of knowledge and skills; (3) professional development; and (4) transition to independence. RESEARCH: Cancer progression involves extensive cell surface remodeling that enables immune evasion but also exposes therapeutic vulnerabilities. However, how these dynamic surface changes shape tumor–immune interactions and fibrosis remains poorly understood. My postdoctoral work has established a novel cell surface proteomics and labeling pipeline that systematically maps the tumor surface proteome across multiple cancer types. This approach identified the urokinase plasminogen activator receptor (uPAR) as a conserved, senescence- and fibrosis-associated antigen enriched in p53-mutant tumors. Using advanced mouse models and a state-of-the-art CAR T cell engineering platform, I developed uPAR-directed CAR T cells that show potent anti-tumor activity with minimal toxicity. Building upon these findings, my proposed research seeks to define and therapeutically exploit senescence- and fibrosis-associated tumor states as new classes of immunotherapy targets. In Aim 1, I will investigate how therapy-induced senescence enhances uPAR CAR T cell activity and develop next-generation CAR designs with improved potency and safety. In Aim 2, I will target tumor-associated fibrosis by eliminating uPAR⁺ fibroblasts and myeloid cells that sustain immunosuppression, and develop dual-targeting strategies to coordinate tumor and stromal clearance. Together, these studies will elucidate how pathological surface remodeling during senescence and fibrosis creates actionable immune targets, establishing a foundation for engineered cell therapies that overcome antigen heterogeneity and fibrotic immune barriers in solid tumors. Vertebrate animal models are necessary to evaluate the antitumor efficacy, safety, tissue trafficking, and immune effects of uPAR-directed CAR T-cell therapies within an intact tumor microenvironment. These complex interactions among tumor, stromal, immune, and normal-tissue compartments, as well as longitudinal therapeutic responses and potential toxicities, cannot be adequately reproduced using in vitro systems alone. ENVIRONMENT: MSKCC provides an ideal environment for me to accomplish my training and research goals, and successfully transition to an independent faculty position at an academic institution. My mentor Dr. Lowe is a world leader in cancer biology, with a particular expertise on senescence, tumor suppressor networks, mouse models, and functional genetics. My co-mentor Dr. Sadelain is a world leader in CAR T cell engineering and therapy. In addition, I have assembled an advisory committee of three established scientists with relevant expertise and strong commitment to mentoring (Drs. Shah, Li, and Zamarin), who will support my transition to independence by providing valuable research and career guidance. Combined with the collaborative environment and rich resources at MSKCC, this support network creates optimal conditions for the successful completion of the proposed research and career development plans.
