Abstract
Abstract Several ongoing clinical trials employ vaccine, immune checkpoint inhibitors and/or adoptive T cell therapy to treat glioblastoma. However, the impact of irradiation as part of the standard of care on the immune microenvironment and response to immunotherapy is ill-defined. In the present study, we analyzed the post-irradiation changes in the GBM immune microenvironment, and further elucidated the impact of fractionated tumor irradiation (FIR) on the efficacy of T cell-mediated immunotherapies in experimental gliomas. FIR boosted the response of orthotopically-implanted GL261 tumors expressing the tumor-associated antigen glycoprotein (gp)100 to a gp100 vaccine. Furthermore, FIR enhanced the infiltration of GL261-gp100 gliomas by adoptively-transferred gp100 T cell receptor-transgenic T cells, which also displayed a more activated and less exhausted phenotype post-irradiation. Single cell transcriptomic studies of tumor-infiltrating CD45+ leukocytes revealed that FIR promotes the expression of leukocyte-endothelial adhesion molecules in T cells, and transcripts encoding proinflammatory M1-like genes in tumor-associated microglia and macrophages. Collectively, our preclinical findings support the use of FIR with to increase response to T cell-based immunotherapies.
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