P030 Myeloid calcineurin in the control of immune checkpoint inhibition in intestinal tumour development. (25th January 2019)

• Record Type: Journal Article
• Authors: Peuker, K; Strigli, A; Južnić, L; Matthiesen, L; Koch, M; Krüger, S; Tauriello, D; Batlle, E; Röcken, C; Hampe, J; Zeissig, S
• Is Part Of: Journal of Crohn's and colitis. Volume 13(2019)Supplement 1
• Page Start: S101
• Page End: S101
• Publication Date: 2019-01-25
• Subjects: Inflammatory bowel diseases -- Periodicals; 616.344005
• DOI: 10.1093/ecco-jcc/jjy222.154
• Languages: English
• ISSNs: 1873-9946

Abstract

Abstract: Background: IBD is a risk factor for colorectal cancer (CRC) development and studies in colitis-associated CRC have delineated pathways through which inflammation promotes tumour development in the intestine. Intriguingly, similar pathways are operative in sporadic CRC and promote tumorigenesis in the absence of overt clinical inflammation. Here, we have investigated the cross-talk between myeloid tumour-infiltrating cells, intestinal epithelial cells and cytotoxic T cells in CRC development, with particular emphasis on the role of calcineurin, a phosphatase with critical roles in immunity and inflammation. Methods: Intestinal tumour development was analysed in ApcMin/+ mice with or without myeloid-specific deletion of calcineurin or the calcineurin-dependent transcription factors nuclear factor of activated T cells (NFAT). Results: Studies of ApcMin/+ mice revealed barrier dysfunction at sites of intestinal adenomas, which was associated with tumour infiltration by the commensal microbiota and microbiota-dependent activation of calcineurin and NFAT in myeloid tumour-infiltrating cells. Myeloid-specific deletion of calcineurin protected mice from tumour development as a consequence of reduced NFAT-dependent transcription of IL-6 and reduced IL-6-dependent activation of STAT3 in epithelial tumour cells. Intriguingly, however, protective effects of impaired STAT3 activation were not epithelial-cell-intrinsic. Instead, we could demonstrate that STAT3 promotes the transcription and epithelial expression of B7-H3 and B7-H4, two co-inhibitory proteins of the B7 family, which inhibit cytotoxic T-cell responses against the tumour. Accordingly, both antibody-mediated inhibition as well as epithelial deletion of B7-H3 and B7-H4 led to increased infiltration of tumours by activated CD8+ T cells and T-cell-mediated protection from tumour development. Conclusions: Our studies reveal a novel pathway of calcineurin-dependent cross-talk between epithelial, myeloid, and lymphoid cells, which promotes tumour development through inhibition of cytotoxic T-cell responses and highlights novel, promising targets for checkpoint inhibition in CRC.