In a murine transplantable glioma model, CD8+ T cell depletion beginning at implantation did not affect tumor growth, but tumors developed in this context had impaired progression when transferred into immunocompetent recipients. Gliomas grown in the absence of CD8+ T cells displayed a more malignant and immunogenic phenotype, with increased genomic instability, activation of MAPK signaling pathways, and cGAS-STING expression. These tumors also showed increased infiltration of innate immune cells, particularly inflammatory macrophages and microglia, which correlated with MAPK signaling – a trend also observed in human glioblastoma patients.
Contributed by Alex Najibi
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.
Author Info: (1) Department of Neurological Surgery, Northwestern University. (2) Biomedical Informatics, Columbia University Medical Center. (3) Department of Neurosurgery, Columbia University
Author Info: (1) Department of Neurological Surgery, Northwestern University. (2) Biomedical Informatics, Columbia University Medical Center. (3) Department of Neurosurgery, Columbia University. (4) Department of Mircobiology and Immunology, Columbia University. (5) Department of Neurological Surgery, Northwestern University. (6) Neurological Surgery, Columbia University. (7) Department of Neurosurgery, University of Texas MD Anderson Cancer Center. (8) Pathology and Cell Biology, Columbia University Medical Center. (9) Department of Neurological Surgery, Northwestern University. (10) Neurological Surgery, Northwestern University. (11) Neurological Surgery, Northwestern University. (12) Northwestern University. (13) Department of Neurological Surgery, Northwestern University Feinberg School of Medicine. (14) Department of Neurological Surgery, Northwestern University Feinberg School of Medicine. (15) Department of Microbiology and Immunology, Columbia University. (16) Department of Microbiology and Immunology, Columbia University. (17) Pathology, Northwestern University, Feinberg School of Medicine. (18) Department of Neurological Surgery, Northwestern University Feinberg School of Medicine. (19) Neurosurgery, University of Texas MD Anderson Cancer Center. (20) Department of Systems Biology, Columbia University Irving Medical Center. (21) Pathology and Cell Biology, Columbia University. (22) Department of Neurological Surgery, Northwestern University Adam.Sonabend@nm.org.
