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

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

doi:10.1101/2024.10.28.620471

bioRxiv · 10.1101/2024.10.28.620471

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

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

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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. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=113 SRC="FIGDIR/small/620471v1_ufig1.gif" ALT="Figure 1"> View larger version (49K): org.highwire.dtl.DTLVardef@13b075borg.highwire.dtl.DTLVardef@601b49org.highwire.dtl.DTLVardef@19f58e4org.highwire.dtl.DTLVardef@84e8bf_HPS_FORMAT_FIGEXP M_FIG C_FIG

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Herbst, M., Koksal, H., Brunn, S., Zanetti, D., Domocos, I., De Stefani, V., Pereira, P., Nater, M., Cecconi, V., van den Broek, M.. 2024-10-31. Cancer-cell-derived cGAMP limits the activity of tumor-associated CD8+ T cells. https://doi.org/10.1101/2024.10.28.620471

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