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Hypoxia drives CD39-dependent suppressor function in exhausted T cells to limit antitumor immunity
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Hypoxia drives CD39-dependent suppressor function in exhausted T cells to limit antitumor immunity
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Journal Article
Hypoxia drives CD39-dependent suppressor function in exhausted T cells to limit antitumor immunity
2023
Overview
CD8
+
T cells are critical for elimination of cancer cells. Factors within the tumor microenvironment (TME) can drive these cells to a hypofunctional state known as exhaustion. The most terminally exhausted T (tT
ex
) cells are resistant to checkpoint blockade immunotherapy and might instead limit immunotherapeutic efficacy. Here we show that intratumoral CD8
+
tT
ex
cells possess transcriptional features of CD4
+
Foxp3
+
regulatory T cells and are similarly capable of directly suppressing T cell proliferation ex vivo. tT
ex
cell suppression requires CD39, which generates immunosuppressive adenosine. Restricted deletion of CD39 in endogenous CD8
+
T cells resulted in slowed tumor progression, improved immunotherapy responsiveness and enhanced infiltration of transferred tumor-specific T cells. CD39 is induced on tT
ex
cells by tumor hypoxia, thus mitigation of hypoxia limits tT
ex
suppression. Together, these data suggest tT
ex
cells are an important regulatory population in cancer and strategies to limit their generation, reprogram their immunosuppressive state or remove them from the TME might potentiate immunotherapy.
Exhausted CD8
+
T cells with diminished effector functions accumulate in tumors. Here, the authors show that hypoxia induces a suppressive phenotype in exhausted T cells and that interfering with hypoxia-mediated CD39 expression limits immunosuppression in the tumor and augments immunotherapy, resulting in arrest of tumor growth.
Publisher
Nature Publishing Group US,Nature Publishing Group
Subject
