Chronic gut inflammation is associated with the development of colorectal cancer (CRC), a leading cause of cancer-related deaths worldwide. The immune system plays a critical role in both the initiation and progression of CRC, with the immunoregulatory cytokine IL-10 exerting pro- and anti-tumorigenic effects. IL-10 is secreted by virtually all immune cells, including myeloid antigen-presenting cells (APC) such as dendritic cells (DC) and macrophages. While DC initiate tumor-specific adaptive immune responses through antigen presentation, macrophages play a complementary role by maintaining mucosal homeostasis. B cell-derived IL-10 appears to promote the development of colitis-associated cancer by fostering pro-tumorigenic macrophages.

To investigate the role of IL-10 signaling in APC during the development of CRC, we used mice deficient in IL-10Rα primarily in DC (IL-10Rα_delCD11c) or in macrophages (IL‑10Rα_delCX3CR1) in the AOM/DSS model of colitis-associated cancer.

Unexpectedly, loss of IL-10 sensing by myeloid APC exacerbated colorectal tumor burden. IL-10Rα_delCD11c and IL-10Rα_delCX3CR1 mice exhibited greater weight loss during acute inflammation and subsequently impaired weight gain during tumorigenesis compared to littermate controls. Persistent colonic inflammation was further evidenced by sustained leukocyte infiltration and shortened, thickened colons on the day of tumor evaluation. In the mesenteric lymph nodes of tumor-bearing mice, migratory and resident DC upregulated MHCI and CD86 expression. scRNA-seq of tumor-infiltrating leukocytes from IL-10Rα_delCD11c mice revealed that CD8⁺ T cells displayed increased expression of inhibitory receptors such as CTLA-4, TIM3, TIGIT, and LAG3, along with reduced IFNγ expression, indicating exhaustion. Chronic antigen exposure of IL-10Rα-deficient DC led to a faster decline of IFNγ production in co-cultured CD8⁺ T cells, confirming the enhanced capability of IL-10Rα-deficient DC to drive CD8⁺ T cell exhaustion.

Future work will further investigate altered immune cell interactions in IL-10Rα_delCD11c and IL-10Rα_delCX3CR1 mice to uncover tumor-promoting signaling pathways, which could help developing immunotherapeutic strategies to improve the treatment of CRC.