Tumor hypoxia represses γδ T cell-mediated antitumor immunity against brain tumors.

The anatomic location and immunologic characteristics of brain tumors result in strong lymphocyte suppression. Consequently, conventional immunotherapies targeting CD8 T cells are ineffective against brain tumors. Tumor cells escape immunosurveillance by various mechanisms and tumor cell metabolism can affect the metabolic states and functions of tumor-infiltrating lymphocytes. Here, we discovered that brain tumor cells had a particularly high demand for oxygen, which affected γδ T cell-mediated antitumor immune responses but not those of conventional T cells. Specifically, tumor hypoxia activated the γδ T cell protein kinase A pathway at a transcriptional level, resulting in repression of the activatory receptor NKG2D. Alleviating tumor hypoxia reinvigorated NKG2D expression and the antitumor function of γδ T cells. These results reveal a hypoxia-mediated mechanism through which brain tumors and γδ T cells interact and emphasize the importance of γδ T cells for antitumor immunity against brain tumors.

Citation

Jang Hyun Park, Hyun-Jin Kim, Chae Won Kim, Hyeon Cheol Kim, Yujin Jung, Hyun-Soo Lee, Yunah Lee, Young Seok Ju, Ji Eun Oh, Sung-Hong Park, Jeong Ho Lee, Sung Ki Lee, Heung Kyu Lee. Tumor hypoxia represses γδ T cell-mediated antitumor immunity against brain tumors. Nature immunology. 2021 Mar;22(3):336-346

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PMID: 33574616

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