Pancreatic ductal adenocarcinoma (PDA), a malignancy refractory to most therapies including immune checkpoint blockade (ICB) therapy, utilizes diverse mechanisms to evade immune clearance. One mechanism involves reduced presentation of tumor specific antigens by Major histocompatibility complex class I (MHC-I) to immune cells. Many cancers alter MHC-I expression via genetic or epigenetic silencing, however changes in MHC-I trafficking can also profoundly influence antigen presentation at the cell surface and is a previously underappreciated mechanism of MHC-I regulation in cancer. My preliminary data uncovers a role for enhanced autophagy/lysosome function in immune evasion through selective targeting of MHC-I molecules for degradation. PDA cells display reduced MHC-I cell surface expression and instead, demonstrate predominant localization within autophagosomes and lysosomes. Notably, autophagy inhibition restores surface MHC-I levels, leading to improved antigen presentation, enhanced anti-tumor T cell response, and reduced tumor growth in syngeneic hosts. Accordingly, autophagy inhibition, either genetically or pharmacologically with Chloroquine (CQ), synergizes with dual ICB (anti-PD1 and anti-CTLA4), and leads to an enhanced anti-tumor immune response. Motivated by this preliminary data, my specific aims will address two fundamental questions underlying the basic biology of MHC-I regulation and altered trafficking to the lysosome in PDA: (1) What are the distinct molecular mechanisms governing MHC-I capture by the autophagy machinery? and (2) Where does capture of MHC-I occur in the cell prior to trafficking to the lysosome for degradation? Results from these studies will lead to a detailed molecular understanding of the underlying properties of PDA cells and potentially other aggressive cancers, that lead to reduced MHC-I mediated antigen presentation.
The development and use of immunotherapy-based strategies that activate the immune system to search and destroy cancer cells has revolutionized cancer therapy for many patients. However, pancreatic ductal adenocarcinoma (PDA), a malignancy refractory to most therapies including immune checkpoint blockade, remains one of the most difficult diseases to treat. Thus, we will define the underlying molecular mechanisms governing defective antigen presentation to identify combination therapy strategies that could be effective in PDA.
