Tyk2 controls immunosurveillance of colorectal cancer liver metastasis

Colorectal cancer liver metastasis (CRLM) is a major clinical problem. However, little is known about immunosurveillance of CRLM. The Janus kinase Tyk2 is involved in several immune processes, but its role in CRLM is unclear. We have developed a murine colorectal cancer (CRC) organoid-based transplantation model to investigate the functions of Tyk2 in CRLM. Organoids with mutations in Apc, Kras, and p53 were injected into the spleen or portal vein of host mice with Tyk2 deletion in different subsets of immune cells as well as into wild-type host mice treated with the Tyk2 inhibitor deucravacitinib. In addition, cancer cell-intrinsic effects on CRLM were investigated using organoids with CRISPR/Cas9-mediated deletion of Tyk2. Our data show that Tyk2 is a key factor controlling CRLM. We found that Tyk2 is not required in cancer cells, macrophages, NK cells, T cells, and Kupffer cells, but controls CRLM via a dendritic cell-dependent mechanism that relies on MHC-I-dependent cross presentation of antigens to CD8+ T cells. Analysis of a scRNA-seq dataset for primary CRC and CRLM revealed that Tyk2 is predominantly expressed in a specific dendritic cell population that is destined to present antigens in tumor-draining lymph nodes. Although our data cannot prove a role for Tyk2 in immune surveillance of CRLM in humans, they should be considered when treating patients with Tyk2 inhibitors.