Microbiota-dependent activation of the myeloid calcineurin-NFAT pathway inhibits B7H3- and B7H4-dependent anti-tumor immunity in colorectal cancer

Kenneth Peuker, Anne Strigli, Daniele V.F. Tauriello, Alexander Hendricks, Witigo von Schönfels, Greta Burmeister, Mario Brosch, Alexander Herrmann, Sandra Krüger, Jessica Nitsche, Lea Južnić, Marc Marius Geissler, Andreas Hiergeist, André Gessner, Jakob Wirbel, Ruby Priyadarshini Ponnudurai, Antje Tunger, Rebekka Wehner, Daniel E. Stange, Jürgen WeitzDaniela E. Aust, Gustavo B. Baretton, Marc Schmitz, Christoph Röcken, Jochen Hampe, Sebastian Hinz, Georg Zeller, Triantafyllos Chavakis, Clemens Schafmayer, Eduard Batlle, Sebastian Zeissig*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

22 Citations (Scopus)

Abstract

Bacterial sensing by intestinal tumor cells contributes to tumor growth through cell-intrinsic activation of the calcineurin-NFAT axis, but the role of this pathway in other intestinal cells remains unclear. Here, we found that myeloid-specific deletion of calcineurin in mice activated protective CD8+ T cell responses and inhibited colorectal cancer (CRC) growth. Microbial sensing by myeloid cells promoted calcineurin- and NFAT-dependent interleukin 6 (IL-6) release, expression of the co-inhibitory molecules B7H3 and B7H4 by tumor cells, and inhibition of CD8+ T cell-dependent anti-tumor immunity. Accordingly, targeting members of this pathway activated protective CD8+ T cell responses and inhibited primary and metastatic CRC growth. B7H3 and B7H4 were expressed by the majority of human primary CRCs and metastases, which was associated with low numbers of tumor-infiltrating CD8+ T cells and poor survival. Therefore, a microbiota-, calcineurin-, and B7H3/B7H4-dependent pathway controls anti-tumor immunity, revealing additional targets for immune checkpoint inhibition in microsatellite-stable CRC.

Original languageEnglish
Pages (from-to)701-717.e7
JournalImmunity
Volume55
Issue number4
DOIs
Publication statusPublished - 12 Apr 2022
Externally publishedYes

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© 2022 Elsevier Inc.

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