CD8+ T-cell-mediated immunoediting influences genomic evolution and immune evasion in murine gliomas.

Purpose: Cancer immunoediting shapes tumor progression by the selection of tumor cell variants that can evade immune recognition. Given the immune evasion and intra-tumor heterogeneity characteristic of gliomas, we hypothesized that CD8+ T-cells mediate immunoediting in these tumors. Experimental Design: We developed retrovirus-induced PDGF+Pten-/- murine gliomas and evaluated glioma progression and tumor immunogenicity in the absence of CD8+ T-cells by depleting this immune cell population. Furthermore, we characterized the genomic alterations present in gliomas that developed in the presence and absence of CD8+ T-cells. Results: Upon transplantation, gliomas that developed in the absence of CD8+ T-cells engrafted poorly in recipients with intact immunity but engrafted well in those with CD8+ T-cell depletion. In contrast, gliomas that developed under pressure from CD8+ T-cells were able to fully engraft in both CD8+ T-cell-depleted mice and immunocompetent mice. Remarkably,gliomas developed in the absence of CD8+ T-cells exhibited increased aneuploidy, MAPK pathway signaling, gene fusions, and macrophage/microglial infiltration, and showed a proinflammatory phenotype. MAPK activation correlated with macrophage/microglia recruitment in this model and in the human disease. Conclusions: Our studies indicate that, in these tumor models, CD8+ T-cells influence glioma oncogenic pathways, tumor genotype, and immunogenicity. This suggests immunoediting of immunogenic tumor clones through their negative selection by CD8+ T-cells during glioma formation.