UNDERSTANDING THE ROLE OF T CELL MEDIATED IMMUNE RESPONSES IN CANCER IMMUNOTHERAPIES

Abstract

The field of cancer immunotherapy has been transformed over the last decade, with a significant emphasis on T cell-based therapies due to their ability to attack cancer cells specifically. However, despite substantial progress in the development of T cell-based cancer immunotherapies, a large proportion of patients do not respond favorably, particularly in ‘cold’ tumors, which are typically categorized by a lack of tumor antigens, and defective antigen-presenting cell (APC) and T cell priming, activation, or infiltration. Methods for characterizing and modulating tumor microenvironments (TME) could help develop future immunotherapies. The current thesis investigates two avenues of research: developing new methods for detecting tumor antigens and developing novel therapeutics to make tumors ‘hot’ and boost anticancer immunity. The first project focuses on discovering class I major histocompatibility complex (MHC-I)-bound tumor antigens that govern the specificity and activation of CD8+ T cells. Traditional methods using mass spectrometry (LC-MS/MS) based MHC-peptide identification suffer from inflated search spaces, leading to limited efficiency and poor statistical power in peptide mapping and identification. The current thesis addresses these shortcomings by employing a targeted database search strategy and developing an accompanying tool, SpectMHC, which is based on previously predicted MHC-I peptides. This unique technique improved the identification rates and statistical power of MHC-I peptides in human and mouse models in an MS-based peptide discovery platform. The later projects focus on utilizing immunogenic cell death (ICD) of cancer, a regulatory form of cell death characterized by enhanced antigenicity and adjuvanticity, to modulate the TME and initiate specific anticancer immune responses mediated by APCs and T cells. We created novel photodynamic therapies that target cancer cells directly via cytotoxic and indirectly via inflammatory responses, induction of the hallmarks of ICD, and activation of dendritic cells resulting in protective anticancer immunity. This research resulted in the development of promising immunogenic photodynamic therapies for the treatment of melanoma, which have the potential to be translated from bench to bedside. Overall, the current thesis presents novel strategies for understanding and inducing T cell-mediated anticancer immune responses.