Virus-specific CD8+ T cells in murine glioblastoma originate from brain resident and circulating memory pools and exhibit bystander activation 2259751

Abstract

Abstract Introduction Tumor-infiltrating CD8+ T cells expressing tissue residency markers (CD69/CD103) correlate with positive prognosis in numerous cancers. While tumor-infiltrating lymphocytes (TILs) were once thought to be largely tumor-specific, T cells specific for common viral infections are prevalent in human tumors and often express CD69 and CD103. Many murine tumor models fail to recapitulate the T cell subsets in human tumors, as they lack both non-tumor-specific T cells and CD103+ resident memory T cells (Trm). As a result, studies of TIL migratory properties paint an incomplete picture. Indeed, the source of these non-tumor specific T cells remains unclear. Methods We established an orthotopic murine glioblastoma (GBM) model with trackable virus-specific CD8+ T cells capable of expressing CD69 and CD103. Using adoptive transfers and depletion strategies, we assessed the contribution and phenotype of circulating memory T cells (Tcircm) and pre-existing Trm to the TIL population by flow cytometry and single-cell RNA sequencing. Results We found that Tcircm infiltrate GBM tumors and upregulate CD69, while pre-existing virus-specific brain Trm constitute the CD69+/CD103+ population. Furthermore, infecting mice bearing GBM tumors showed that new infection-specific Trm can form in established tumors and express CD69 and CD103. To better understand the role of these cells in brain tumors, we evaluated activation markers at early timepoints following adoptive transfer of Tcircm into tumors. Within 24 hours, we observed increased cytotoxic molecule production and enhanced activation marker expression, suggesting that newly infiltrating virus-specific T cells in tumors are activated in a bystander, non-TCR manner. Conclusion Ongoing efforts focus on identifying the factors driving bystander activation of virus-specific TILs and their impact on tumor control. Overall, this study broadens our understanding of tumor immunosurveillance and provides insights for the development of novel T cell-based immunotherapies. Funding Source NCI R01CA269455 Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)