Interleukin-36α inhibits colorectal cancer metastasis by enhancing the infiltration and activity of CD8+ T lymphocytes

Colorectal cancer is one of the deadliest cancers, and the discovery of new diagnostic biomarkers and therapeutic targets is vital. Interleukin-36 alpha (IL-36 alpha) is a proinflammatory factor that can initiate the inflammatory response and promote the systemic T helper-1 (Th1) immune response. In this study, we investigated the immunological role of IL-36 alpha in CRC. We found that IL-36 alpha was downregulated in human CRC tissues. Patients with high IL-36 alpha levels showed better survival and low IL-36 alpha expression was significantly associated with greater tumor distal metastasis and TNM stage. We constructed two cell lines overexpressing IL-36 alpha (CT26-IL-36 alpha and HT29-IL-36 alpha cells). In vitro assays revealed that IL-36 alpha overexpression reduced the proliferation, migration, and invasion of CT26-IL-36 alpha, and HT29-IL-36 alpha cells. Using CT26-vector and CT26-IL-36 alpha tumor mouse model and lung metastasis models, we found that IL-36 alpha overexpression elicited a significant antitumor effect and inhibited lung metastasis in vivo. These inhibitory effects were associated with an increase in the number of CD3(+)CD8(+) T lymphocytes within the tumor tissue as well as increased cytokine production in CD8(+) T lymphocytes present in the tumor, spleen, and draining lymph nodes. Furthermore, we revealed that CT26-IL-36 alpha cells enhanced the secretion of CXCL10 and CXCL11 from chemotactic CD8(+) T lymphocytes, as compared with CT26-vector cells. Taken together, these results suggest that IL-36 alpha is a promising therapeutic agent for targeting CRC by promoting the activation, proliferation, and tumor infiltration of T lymphocytes.

Automated summary

Colorectal cancer is one of the deadliest cancers, and the discovery of new diagnostic biomarkers and therapeutic targets is crucial. IL-36 alpha was found to be downregulated in human CRC tissues, and high levels of IL-36 alpha were associated with better survival rates. Overexpression of IL-36 alpha inhibited the proliferation, migration, and invasion of cancer cells and promoted the activation, proliferation, and infiltration of T lymphocytes. These results suggest that IL-36 alpha could be a promising therapeutic agent for targeting CRC.