BSBM-19 CROSS-PRESENTATION BY TUMOR-ASSOCIATED MACROPHAGES MEDIATES THE TRANSITION FROM PROGENITOR TO TERMINAL T CELL EXHAUSTION IN PRIMARY AND METASTATIC BRAIN TUMORS

Abstract Glioblastoma (GBM) and brain metastases remain largely resistant to immunotherapeutic intervention. T cell exhaustion, a differentiation state characterized by loss of function persistence, contributes this resistance. Two exhaustion subsets, progenitor (Tex_prog) terminal (Tex_term), have been identified, where only Tex_prog responsive immunotherapy. To date, the dynamics characteristics these exhausted populations in GBM unclear. Herein, we identify striking murine model throughout tumor progression. We elucidate requirements for Tex_term transition through characterization progression at RNA (paired scRNA TCR sequencing) protein level (flow-cytometry). are enriched pathways migration, cell-cell adhesion, differentiation, whereas primarily upregulate cytotoxic pathways. TCRseq revealed that clonal expansion is concentrated cluster, suggesting link between proliferation response antigen. Likewise, defined necessity hematopoietic antigen presentation, but not tumor-derived presentation transition. Of presenting cells TME, tumor-associated macrophages (TAM) had greatest expression tumor-antigen loaded MHC I, illustrating their capacity cross-present. By depleting TAM, observed disruption Similar results were seen subcutaneous intracranial melanoma, highlighting role TAM process across histology location. Lastly, identified additional inflammatory interactions mice humans may contribute phenomenon. Taken together, define models primary metastatic tumors, critical mediator Tex_prog. extend findings human data better complex interactions, which aim leverage overcome immunotherapy