o:1721 Tyk2 is a tumor suppressor in colorectal cancer en Janus kinase Tyk2 is implicated in cancer immune surveillance, but its role in solid tumors is not well defined. We used Tyk2 knockout mice (Tyk2Δ/Δ) and mice with conditional deletion of Tyk2 in hematopoietic (Tyk2ΔHem) or intestinal epithelial cells (Tyk2ΔIEC) to assess their cell type-specific functions in chemically induced colorectal cancer. All Tyk2-deficient mouse models showed a higher tumor burden after AOM-DSS treatment compared to their corresponding wild-type controls (Tyk2+/+ and Tyk2fl/fl), demonstrating tumor-suppressive functions of Tyk2 in immune cells and epithelial cancer cells. However, specific deletion of Tyk2 in hematopoietic cells or in intestinal epithelial cells was insufficient to accelerate tumor progression, while deletion in both compartments promoted carcinoma formation. RNA-seq and proteomics revealed that tumors of Tyk2Δ/Δ and Tyk2ΔIEC mice were immunoedited in different ways with downregulated and upregulated IFNγ signatures, respectively. Accordingly, the IFNγ-regulated immune checkpoint Ido1 was downregulated in Tyk2Δ/Δ and upregulated in Tyk2ΔIEC tumors, although both showed reduced CD8+ T cell infiltration. These data suggest that Tyk2Δ/Δ tumors are Ido1-independent and poorly immunoedited while Tyk2ΔIEC tumors require Ido1 for immune evasion. Our study shows that Tyk2 prevents Ido1 expression in CRC cells and promotes CRC immune surveillance in the tumor stroma. Both of these Tyk2-dependent mechanisms must work together to prevent CRC progression. Animals; Colitischemically induced; Colorectal Neoplasmsgeneticspathology; Indoleamine-Pyrrole 2,3,-Dioxygenasemetabolism; Intestinal Mucosametabolismpathology; Janus Kinasesmetabolism; Mice; Mice, Knockout 1552099 10.1080/2162402X.2022.2127271 2023-06-14T08:53:23.549Z 44 yes 46 Stefan Moritsch Medical University of Vienna / Comprehensive Cancer Center person Robert Eferl Medical University of Vienna / Comprehensive Cancer Center person 0000-0002-6074-7144 Birgit Strobl University of Veterinary Medicine Vienna person 0000-0001-5716-3212 Mathias Müller University of Veterinary Medicine Vienna person 0000-0002-7879-3552 Christopher Gerner University of Vienna / Medical University of Vienna person Dietmar Herndler-Brandstetter Medical University of Vienna / Comprehensive Cancer Center person Lukas Kenner Medical University of Vienna person 0000-0003-2184-1338 Thomas Mohr Medical University of Vienna / Comprehensive Cancer Center person Emilio Casanova Medical University of Vienna / Comprehensive Cancer Center person Gerald Timelthaler Medical University of Vienna / Comprehensive Cancer Center person Daniela Zwolanek Medical University of Vienna / Comprehensive Cancer Center person Lukas Janker University of Vienna / Medical University of Vienna person Irene Scharf Medical University of Vienna / Comprehensive Cancer Center person Bernadette Mödl Medical University of Vienna / Comprehensive Cancer Center person Maria Sibilia Medical University of Vienna / Comprehensive Cancer Center person application/pdf 981232 https://phaidra.vetmeduni.ac.at/o:1721 no yes 16 70 1552253 Oncoimmunology 11 1 Taylor & Francis Inc 2022