Title
Tyk2 is a tumor suppressor in colorectal cancer
Author
Stefan Moritsch
Center for Cancer Research, Medical University of Vienna & Comprehensive Cancer Center
Bernadette Mödl
Center for Cancer Research, Medical University of Vienna & Comprehensive Cancer Center
Irene Scharf
Center for Cancer Research, Medical University of Vienna & Comprehensive Cancer Center
... show all
Abstract
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.
Keywords
colitis-associated colorectal
cancerazoxymethane AOMdextran sulfate salt DSSindoleamine 23-dioxygenase 1 Ido1interferon gamma
Object type
Language
English [eng]
Persistent identifier
phaidra.univie.ac.at/o:1674689
Appeared in
Title
OncoImmunology
Volume
11
Issue
1
ISSN
2162-402X
Issued
2022
Publication
Informa UK Limited
Version type
Date issued
2022
Access rights
Rights
Rights statement
© 2022 The Author(s)
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