SUMMARY
Skin cancer is the most common cancer in the United States, among which melanoma is the most serious type with high mortality rate. Despite the critical role of CD8+ T cells in tumor clearance, their functions in the tumor microenvironment (TME) are impaired by immunosuppressive cells/cytokines, inhibitory receptors, and metabolic restriction. Targeting these pathways were shown to promote tumor clearance, yet unknown mechanisms may still exist curtailing the T cell responses. T cell activation has been shown to be largely determined by the in situ mechanokinetic properties of the binding of T cell receptor (TCR) to peptide-major histocompatibility complex (pMHC), which are sensitive to perturbations of the cellular environment. Our preliminary studies have shown that the molecular interactions involved in T cell antigen recognition are altered in the TME. The present thesis will study the extent of this alteration, how such alteration consequentially suppresses T cell effector functions, and what the underlying mechanisms are. This study aims to address these questions with animal models, highly-sensitive biomechanical assays of single molecules, and other cellular and bimolecular approaches. The outcome will greatly enhance our understanding of the impaired anti-tumor T cell responses and inspire novel strategies for cancer immunotherapy.