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Video

Tumor Microenvironment

Session: Abstract Concurrent Session: Pediatrics I

TMIC-13 - Exhausted CD8+ T cells maintain low-grade gliomas in Nf1-mutant mice.

Friday, November 17, 2023
4:45 PM – 4:50 PM PT
Location: Room 121-122
Non-CME

    Oral Abstract Presenter(s)

  • Rasha Barakat

    Washington University School of Medicine
    St Louis, Missouri, United States

    • Author(s)

  • JC

    Jit Chatterjee

    Washington University School of Medicine
    St. Louis, United States

  • RM

    Rui Mu

    Washington University School of Medicine
    St Louis, United States

  • XQ

    Xuanhe Qi

    Washington University School of Medicine
    St Louis, United States

  • OC

    Olivia Cobb

    Washington University School of Medicine
    St Louis, Missouri, United States

  • KG

    Karen Gao

    Washington University School of Medicine
    St Louis, Missouri, United States

  • XG

    Xingxing Gu

    Washington University School of Medicine
    St Louis, United States

  • IS

    Igor Smirnov

    Washington University School of Medicine
    St Louis, United States

  • JK

    Jonathan Kipnis

    Washington University School of Medicine
    St Louis, United States

  • David H. Gutmann

    Washington University School of Medicine
    St. Louis, Missouri, United States

T cells are minor cellular constituents of the brain tumor microenvironment, but have recently been shown to play critical roles in glioma pathobiology and treatment. Previous studies from our laboratory have shown that T cells are required for the formation and growth of low-grade gliomas (LGGs) in murine models of the Neurofibromatosis type 1 (NF1) tumor predisposition syndrome. To better characterize the immune landscape of these pediatric low-grade tumors, we leveraged single cell RNA sequencing of human pediatric pilocytic astrocytomas and genetically engineered mouse LGG (Nf1-optic glioma) models. First, we showed that both human and murine LGGs contain a CD8+ T cell population expressing PD-1 and TIGIT, similar to conventional exhausted T cell populations. Second, these PD-1+/TIGIT+ CD8+ T cells are actively recruited to the tumor site by Ccl2 where they dictate tumorigenesis through the elaboration of Ccl4, a cytokine necessary for microglia Ccl5-mediated support of Nf1-OPG growth. As such, Ccl4 expression was enriched in PD-1+/TIGIT+ CD8+ T cells relative to all other T cell populations within these tumors. Third, this “exhausted” CD8+ T cell population was exclusively present in the optic nerves, but not in the blood, dura, or deep cervical nodes of optic glioma-bearing mice. Fourth, targeting this PD1+/TIGIT+ exhausted CD8+ T cell population with immune checkpoint monoclonal antibody inhibitors reduced CD8+ T cell tumoral recruitment, Ccl4 production, and optic glioma growth. Collectively, these findings establish an obligate role for PD-1+/TIGIT+ CD8+ T cells in Nf1-optic glioma control and suggest that immune checkpoint modulation may be useful for the treatment of LGGs in children.