Tumor microenvironmental stress modulates membrane trafficking to regulate T cell receptor complex aggregation in Epithelial Ovarian Cancer 3967

Abstract Description High-grade serous ovarian cancer (HGSOC) remains refractory to current immunotherapeutics despite its immunogenicity. Here we describe a novel mechanism in HGSOC in which aberrant endosomal trafficking promotes disruptions in T cell receptor (TCR) nanoclustering to drive T cell paralysis in HGSOC through functionally impaired TCR:pMHC avidities. We have identified a poorly characterized molecule, BLTP3A, as instrumental in impairing immune synapse formation in tumor beds by shuttling antigen-specific TCR complexes to lysosomes for their degradation. We found that BLTP3A is aberrantly expressed in tumor infiltrating T cells through an ATF4-dependent mechanism, where it associates with RAB7+ endosomes and the endosomal cargo-retrieval retromer complex. Critically, a single nucleotide polymorphism (M1098T) in BLTP3A is commonly found in HGSOC. Leveraging multiplex IF, we found that HGSOCs expressing BLTP3AM1098T demonstrate elevated Granzyme B+ effector T cells in tumor epithelial islets, while the conditional ablation of Bltp3a in post-thymic T cells results in more effective antitumor T cell responses in murine models. Mechanistically, BLTP3A impairs TCR complex recycling to the cell surface from late endosomes in tumor beds, leading to lysosomal degradation of antigen-reactive TCR complexes and promoting tumor-immune evasion. Collectively, this work reveals a novel immunosuppressive mechanism in HGSOC and the potential of silencing BLTP3A for engineered T cell therapeutics. Funding Sources The Pershing Square Sohn Cancer Research Alliance Ovarian Cancer Research Alliance V Foundation American Cancer Society The New Jersey Commission on Cancer Research (NJCCR) Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)