IDO1+ Paneth cells promote immune escape of colorectal cancer

• Published in: Communications biology 2020-05, Vol.3 (1), p.252, Article 252
• Main Authors: Pflügler, Sandra, Svinka, Jasmin, Scharf, Irene, Crncec, Ilija, Filipits, Martin, Charoentong, Pornpimol, Tschurtschenthaler, Markus, Kenner, Lukas, Awad, Monira, Stift, Judith, Schernthanner, Marina, Bischl, Romana, Herndler-Brandstetter, Dietmar, Glitzner, Elisabeth, Moll, Herwig P., Casanova, Emilio, Timelthaler, Gerald, Sibilia, Maria, Gnant, Michael, Lax, Sigurd, Thaler, Josef, Müller, Mathias, Strobl, Birgit, Mohr, Thomas, Kaser, Arthur, Trajanoski, Zlatko, Heller, Gerwin, Eferl, Robert
• Format: Article
• Language: English
• Subjects: 38/91; 45/41; 631/67; 631/67/1504/1885; 631/67/580; 64/60; 96/95; Animals; Biology; Biomedical and Life Sciences; Cancer; Clonal deletion; Colorectal cancer; Colorectal carcinoma; Colorectal Neoplasms - etiology; Colorectal Neoplasms - immunology; Colorectal Neoplasms - metabolism; Colorectal Neoplasms - pathology; Dioxygenase; Gene expression; Immune checkpoint; Immune evasion; Immune Tolerance - immunology; Immunosuppression; Immunosurveillance; Immunotherapy; Indoleamine-Pyrrole 2,3,-Dioxygenase - genetics; Indoleamine-Pyrrole 2,3,-Dioxygenase - metabolism; Intestinal Neoplasms - immunology; Intestinal Neoplasms - metabolism; Intestinal Neoplasms - pathology; Intestine; Life Sciences; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Paneth cells; Paneth Cells - immunology; Stat1 protein; STAT1 Transcription Factor - physiology; Stem cells; Stroma; Tumor cells; Tumors
• ISSN: 2399-3642; 2399-3642
• DOI: 10.1038/s42003-020-0989-y

Tumors have evolved mechanisms to escape anti-tumor immunosurveillance. They limit humoral and cellular immune activities in the stroma and render tumors resistant to immunotherapy. Sensitizing tumor cells to immune attack is an important strategy to revert immunosuppression. However, the underlying mechanisms of immune escape are still poorly understood. Here we discover Indoleamine-2,3-dioxygenase-1 (IDO1) + Paneth cells in the stem cell niche of intestinal crypts and tumors, which promoted immune escape of colorectal cancer (CRC). Ido1 expression in Paneth cells was strictly Stat1 dependent. Loss of IDO1 + Paneth cells in murine intestinal adenomas with tumor cell-specific Stat1 deletion had profound effects on the intratumoral immune cell composition. Patient samples and TCGA expression data suggested corresponding cells in human colorectal tumors. Thus, our data uncovered an immune escape mechanism of CRC and identify IDO1 + Paneth cells as a target for immunotherapy. Pflügler, Svinka et al. identify a subset of Paneth cells in mouse intestinal crypts and tumors, which express the immune checkpoint molecule Ido1 in a Stat1-dependent manner and promote tumor growth. Gene expression data from human colorectal cancer (CRC) suggest that a similar population is present in human cancer and opens the door for further studies of immune escape mechanisms in CRC.