Titel (eng)

Tyk2 is a tumor suppressor in colorectal cancer

Autor*in

Stefan Moritsch   Medical University of Vienna / Comprehensive Cancer Center

Maria Sibilia   Medical University of Vienna / Comprehensive Cancer Center

Robert Eferl   Medical University of Vienna / Comprehensive Cancer Center

Birgit Strobl   University of Veterinary Medicine Vienna

Mathias Müller   University of Veterinary Medicine Vienna

Christopher Gerner   University of Vienna / Medical University of Vienna

Dietmar Herndler-Brandstetter   Medical University of Vienna / Comprehensive Cancer Center

Lukas Kenner   Medical University of Vienna

Thomas Mohr   Medical University of Vienna / Comprehensive Cancer Center

Emilio Casanova   Medical University of Vienna / Comprehensive Cancer Center

Gerald Timelthaler   Medical University of Vienna / Comprehensive Cancer Center

Daniela Zwolanek   Medical University of Vienna / Comprehensive Cancer Center

Lukas Janker   University of Vienna / Medical University of Vienna

Irene Scharf   Medical University of Vienna / Comprehensive Cancer Center

Bernadette Mödl   Medical University of Vienna / Comprehensive Cancer Center

Verlag

Taylor & Francis Inc

Beschreibung (eng)

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.

Sprache des Objekts

Englisch

Datum

2022

Rechte

Dieses Werk bzw. dieser Inhalt steht unter einer
CC BY 4.0 - Creative Commons Namensnennung 4.0 International Lizenz.

CC BY 4.0 International

http://creativecommons.org/licenses/by/4.0/

Klassifikation

Animals; Colitischemically induced; Colorectal Neoplasmsgeneticspathology; Indoleamine-Pyrrole 2,3,-Dioxygenasemetabolism; Intestinal Mucosametabolismpathology; Janus Kinasesmetabolism; Mice; Mice, Knockout

Mitglied in der/den Collection(s) (1)