Inhibition of IL-1β in combination with conventional chemotherapy improves the outcome of CRC treatment

The tumor microenvironment consists of tumor, immune, stromal, and inflammatory cells, which produce cytokines, growth factors and adhesion molecules that promote tumor progression and metastasis. IL-1 is an upstream cytokine that controls inflammation by inducing cytokine/chemokine networks and promoting immunosuppression in the tumor microenvironment, thus leading to tumor progression. We found that in mice deficient in IL-1β, colorectal cancer develops more slowly than in control mice. In IL-1β KO mice, we noted decreased angiogenesis and an increase in the immune response, such as recruitment of CD8-positive cells into the tumor site. Based on these results, we applied therapeutic approaches using anti-IL-1β antibodies in mice that were injected orthotopically with murine colon cancer cells into the cecum. Antibodies were used alone or in combination with standard chemotherapy protocols. We found that anti-IL-1β alone did not inhibit tumor growth but chemotherapy (FolFox) or a combination of FolFox with anti-IL-1β antibodies led to a reduction in the size of the local tumor. Nevertheless, histological examination revealed a high number of micrometastases in livers of mice treated with only FolFox. Fewer micrometastases were found in untreated mice or in mice that received only anti-IL-1β antibodies. Interestingly, there were dramatically fewer micrometastases in mice receiving the combination therapy. The appearance of liver macrometastases was observed only in mice treated with FolFox alone. To elucidate the mechanisms of chemotherapy-induced liver metastasis in our model, we assessed the expression of various pro-inflammatory cytokines in local tumors and at the metastatic site. We observed inhibition of IL-1α and IL-1β after administration of chemotherapy alone or in combination with anti-IL-1β antibodies in local tumors. In contrast, in liver tissue, treatment with only FolFox induced increased expression and secretion of both IL-1 agonistic molecules and other pro-inflammatory molecules. On the other hand, combination treatment led to a decrease in local and systemic inflammation. It is clear that anti-tumor therapy is complex and varies depending on differences in the microenvironment of local tumors and metastasis. Addition of anti-IL-1β antibodies to standard chemotherapy protocols may be a promising approach in patients with colorectal cancer for prevention of metastases development.