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

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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-+
Issue number4
Publication statusPublished - 12 Apr 2022

External IDs

WOS 000791419000004
Scopus 85127660342
Mendeley a3f0904f-e6ca-3b4c-a671-2a843fe7b2dc
unpaywall 10.1016/j.immuni.2022.03.008
PubMed 35364006


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