Interrogating the role of BLTP3A in organizing protective immunity in ovarian cancer

Rutgers Biomedical And Health Sciences, Newark NJ

Investigators

Abstract

ABSTRACT Epithelial ovarian cancer is the deadliest gynecological malignancy in the U.S., with advanced high-grade serous ovarian cancer (HGSOC) patients facing a 5-year survival rate of about 30%. Although T cell infiltration into tumor epithelial islets is linked to prolonged survival, the mechanisms behind these protective immune responses remain poorly understood. My dissertation investigates the tumor cell-intrinsic role of a novel tumor microenvironmental stress-response molecule, BLTP3A, in HGSOC. We identified a germline nonsynonymous SNP, rs13205210 (M1098T), in BLTP3A that is associated with a dramatic survival benefit for HGSOC patients. This mutation is also linked to the development of systemic lupus erythematosus (SLE), suggesting M1098T BLTP3A may provoke enhanced antitumor immunity in HGSOC. Under Dr. Payne's supervision, I demonstrated that HGSOC tumors expressing M1098T-BLTP3A exhibit elevated effector T cells within tumor beds. To elucidate BLTP3A's function, I confirmed its elevated expression in malignant epithelial cells and generated a conditional Bltp3a knockout mouse model. Remarkably, Bltp3a-ablated tumors showed superior survival through a CD8+ T cell-dependent mechanism. Mechanistically, we discovered that BLTP3A interacts with RAB7 and the HOPS complex, acting as a RAB7 effector that may promote autophagosome-lysosome fusion. As such, Aim 1 of this proposal focuses on unraveling the mechanisms by which BLTP3A influences immune cell dynamics, within the tumor microenvironment. During the F99 phase, I will receive rigorous training under Dr. Payne’s mentorship in single-cell data analysis, enabling high-resolution profiling of tumor-infiltrating immune cells. Additionally, I will work closely with Dr. Sant’Angelo and Dr. Payne to gain expertise in secretome and proteomics analyses, mapping immune signatures modulated by BLTP3A ablation. To further understand BLTP3A’s role in autophagosome and lysosomal fusion, I will train in Dr. White's lab. Mastering these advanced methodologies will equip me with the skills for conducting complex, integrative analyses, essential for my transition to independent research during the K00 phase. A critical skillset gap that Aim 2 will address is my ability to thoroughly investigate immune cell interactions within the ovarian tumor microenvironment, leveraging advanced spatial transcriptomics alongside multi-omics approaches, with a focus on proteomics and metabolomics. To bridge this gap, I will seek a postdoctoral lab equipped to provide training in both foundational and state-of-the- art techniques during the K00 phase. This work will establish a robust mechanistic framework for understanding BLTP3A’s role as a regulator of tumor microenvironment interactions, while also advancing my journey toward independence as a cancer immunology investigator