Genetic and epigenetic determinants of cancer cell-intrinsic immune evasion in nasopharyngeal carcinoma

Nasopharyngeal cancer (NPC) is a deadly malignancy that exhibits exceptionally high incidence rates in parts of Asia and Southeast Asia but is uncommon in the rest of the world. While the precise mechanisms underlying the distinctive ethnic and geographical distribution of NPC have yet to be fully described, recent advancements in cancer genomics and deconvolution algorithms have provided key insights into the aetiology of NPC. A key finding has been the observation that immunosuppression often occurs in NPCs through multiple distinct pathways, including the exhaustion of cytotoxic T cells, defects in type I interferon genes and overexpression of viral proteins that inhibit innate immune response. While targeted therapies have been investigated in clinical studies with limited success, immunotherapy strategies have demonstrated promising, albeit modest activity in NPCs. Thus, in this study, we aim to identify genetic and epigenetic alterations that may be responsible for acquired resistance towards cytotoxic T lymphocytes (CTLs) in NPCs. We will model immune evasion in vitro by repeatedly exposing well-characterized NPC cell lines to activated CD8+ CTLs until the cells acquire significant resistance towards CTL-mediated cytotoxicity. By characterizing the epigenetic and genetic differences between CTL-resistant and non-resistant cells, we hope to identify cellular events that could lead to persistent CTL resistance. The importance of key targets identified through genome and epigenome-wide methods will be validated by gene or region-specific epigenetic editing, gene reconstitution or gene silencing techniques. The utility of these targets as prognostic or cancer biomarkers will be evaluated by mining publicly available and collaborator-generated datasets from NPC or head and neck cancer patients. Taken together, we expect that this study will delineate the cellular events that lead to or accompany immune evasion in NPCs, providing novel insights into the aetiology of NPC and potential avenues for NPC treatment and prevention.