Cancer-cell-derived cGAMP limits the activity of tumor-associated CD8+ T cells

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Cancer-cell-derived cGAMP limits the activity of tumor-associated CD8+ T cells

Authors

Herbst, M.; Koksal, H.; Brunn, S.; Zanetti, D.; Domocos, I.; De Stefani, V.; Pereira, P.; Nater, M.; Cecconi, V.; van den Broek, M.

Abstract

Using a mouse tumor model with inducible cancer-cell-intrinsic cGAS expression, we show that cancer-cell-derived cGAMP is essential and sufficient to trigger a sustained type I interferon response within the tumor microenvironment. This led to improved CD8+ T cell-dependent tumor restriction. However, cGAMP limits the proliferation, survival, and function of STING-expressing but not of STING-deficient CD8+ T cells. In vivo, STING deficiency in CD8+ T cells enhanced tumor restriction. Consequently, cancer-cell-derived cGAMP both drives and limits the anti-tumor potential of CD8+ T cells. Mechanistically, T cell-intrinsic STING is associated with pro-apoptotic and antiproliferative gene signatures. Our findings suggest that STING signaling acts as a checkpoint in CD8+ T cells that balances tumor immunity.

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