Dysfunctional BLTP3A enhances anti-tumor immunity via autophagic regulation in High-Grade Serous Ovarian Cancer (HGSOC) 4115

Abstract Description While T cell infiltration into HGSOC correlates with improved patient outcomes, the mechanisms regulating immune orchestration in this disease remain poorly understood. We identified BLTP3A, a poorly characterized member of bridge-like transfer protein family, as a key regulator of immune activity in HGSOC. Notably, we found a germline single nucleotide polymorphism (M1098T) in BLTP3A to be significantly associated with prolonged survival in HGSOC. BLTP3AM1098T is also linked to systemic lupus erythematosus development, suggesting a role in immune modulation. We discovered that HGSOC patients expressing BLTP3AM1098T exhibited higher levels of cytotoxic CD3+ T cells in their tumor beds. In a murine model, Blpt3a-deficient ovarian tumors demonstrated improved survival and increased activity of effector and memory CD8+ T cells and CXCL9+ macrophages. Depletion of CD8+ T cells eliminated this survival advantage, highlighting their critical role. Further investigations revealed that BLTP3A is transcriptionally regulated by ATF4 and interacts with RAB GTPases and the HOPS complex. As such, BLTP3A deficiency impaired autophagic flux, activated NF-κB signaling, and elevated pro-inflammatory cytokines. Our findings suggest dysfunctional BLTP3A disrupts autophagic processes in cancer cells under stress, enhancing anti-tumor immunity through increased inflammatory signaling. Modulating BLTP3A-responsive pathways may offer a novel strategy to potentiate protective immunity in HGSOC. Funding Sources Rutgers Cancer Institute; OCRA; V Foundation; Pershing square SOHN Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)