Identification of a stem cell-specific secretory immune regulatory ligand 3092

Abstract Description Immunotherapies have revolutionized cancer treatment, yet subsets of patients with squamous cell carcinomas (SCCs) experience relapse. Recent research highlighted the roles of a group of tumor-initiating cells (TICs) in driving the relapse of both cutaneous (CSCCs) and head and neck (HNSCCs) SCCs. These TICs exhibit superior resistance to anti-tumor immunity despite intact antigen presentation, however, they compose less than 5% of the total tumor cell population so their unique immune resistance mechanisms have been largely overlooked. This study aims to uncover TIC-specific immune resistance pathways. By analyzing single-cell RNA-seq data profiling gene signatures of various tumor populations in CSCCs, we identified cytotoxic T lymphocyte antigen 2a (Ctla2a) was specifically activated in TICs. Ctla2a is characterized as a cysteine peptidase inhibitor and has high homology to the I29 inhibitory domain of mouse and human cathepsins. Silencing Ctla2a in SCCs reduced tumor growth, enhanced CD8 T cell infiltration, and elevated antigen-specific cytotoxicity. We have found that the conditioned medium collected from SCC cells overexpressing Ctla2a is sufficient to blunt cytokine production in CD8 T cells. Altogether, these results suggest that Ctla2a can be secreted by TICs to perform moonlighting functions and modulate CD8 T cell anti-tumor cytotoxicity. This interaction may serve as a target for next-generation immunotherapy that is able to blunt TIC-specific immune resistance. Funding Sources NIH R01CA285786; NCI 1F99CA294257-01 Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)