The role of IL-1β in Colorectal Cancer and its related metastasis

Colorectal cancer (CRC) is the third leading cause of cancer, with high mortality due to metastasis development. Treatment with chemotherapy frequently results in chemo-resistance. Thus, finding key molecules in the tumor microenvironment (TME) is essential to develop novel anti-cancer approaches.

IL-1β is a major pro-inflammatory cytokine that induces local and systemic inflammatory cascades, which promote cell infiltration into tumor sites. To assess the effects of IL-1 on the development of CRC and its related metastasis, we used the model of orthotopic injection of murine CRC (MC38) cells into C57BL/6 mice or mice deficient in IL-1β.

Our findings show that IL-1β deficiency in the TME leads to a delay in local tumor growth and a decrease in metastasis. A reduction of pro-inflammatory molecules accompanying a decrease in recruitment of monocytes and MDSCs was observed in local tumors obtained from IL-1β KO mice. In contrast, there was an increase in DCs, CD4- and CD8-positive cells, and an increase in the expression of anti-tumor components.

In addition, treating mice with chemotherapy in combination with anti-IL-1 antibodies leads to a decrease in both local CRC and liver metastasis in mice. Indeed, in tumors excised from mice treated with anti-IL-1β antibodies in combination with chemotherapy, the expression of IL-1α, IL-1R, and some angiogenic factors were decreased. This therapy also reduces the recruitment of inflammatory cells and expression of CCR5 and its ligands.

Based on our findings, we hope that inhibition of IL-1β together with standard chemotherapy or immunotherapy treatment will significantly improve treatment in CRC.