phaidra.vetmeduni.ac.at o:1721 DOI 10.1080/2162402X.2022.2127271 Tyk2 is a tumor suppressor in colorectal cancer 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. eng Animals; Colitischemically induced; Colorectal Neoplasmsgeneticspathology; Indoleamine-Pyrrole 2,3,-Dioxygenasemetabolism; Intestinal Mucosametabolismpathology; Janus Kinasesmetabolism; Mice; Mice, Knockout 2023-06-14T09:31:16.696Z LOMv1.0 Author BEGIN:VCARD VERSION:3.0 N:Moritsch;Stefan; FN:Stefan Moritsch END:VCARD BEGIN:VCARD VERSION:3.0 N:Sibilia;Maria; FN:Maria Sibilia END:VCARD BEGIN:VCARD VERSION:3.0 N:;; FN: END:VCARD BEGIN:VCARD VERSION:3.0 N:Eferl;Robert; FN:Robert Eferl X-ORCID:https://orcid.org/0000-0002-6074-7144 END:VCARD BEGIN:VCARD VERSION:3.0 N:Strobl;Birgit; FN:Birgit Strobl X-ORCID:https://orcid.org/0000-0001-5716-3212 END:VCARD BEGIN:VCARD VERSION:3.0 N:Müller;Mathias; FN:Mathias Müller X-ORCID:https://orcid.org/0000-0002-7879-3552 END:VCARD BEGIN:VCARD VERSION:3.0 N:Gerner;Christopher; FN:Christopher Gerner END:VCARD BEGIN:VCARD VERSION:3.0 N:Herndler-Brandstetter;Dietmar; FN:Dietmar Herndler-Brandstetter END:VCARD BEGIN:VCARD VERSION:3.0 N:Kenner;Lukas; FN:Lukas Kenner X-ORCID:https://orcid.org/0000-0003-2184-1338 END:VCARD BEGIN:VCARD VERSION:3.0 N:Mohr;Thomas; FN:Thomas Mohr END:VCARD BEGIN:VCARD VERSION:3.0 N:Casanova;Emilio; FN:Emilio Casanova END:VCARD BEGIN:VCARD VERSION:3.0 N:Timelthaler;Gerald; FN:Gerald Timelthaler END:VCARD BEGIN:VCARD VERSION:3.0 N:Zwolanek;Daniela; FN:Daniela Zwolanek END:VCARD BEGIN:VCARD VERSION:3.0 N:Janker;Lukas; FN:Lukas Janker END:VCARD BEGIN:VCARD VERSION:3.0 N:Scharf;Irene; FN:Irene Scharf END:VCARD BEGIN:VCARD VERSION:3.0 N:Mödl;Bernadette; FN:Bernadette Mödl END:VCARD https://w3id.org/kim/hcrt/scheme https://w3id.org/kim/hcrt/text Textdokument Text LOMv1.0 yes https://creativecommons.org/licenses/by/4.0 application/pdf 981232 https://phaidra.vetmeduni.ac.at/o:1721 https://phaidra.vetmeduni.ac.at/api/object/o:1721/thumbnail LOMv1.0 discipline