Are we mature enough to apply anti-IL-1beta therapy in cancer patients?

Introduction- Targeting the tumor microenvironment, except of immune checkpoint blockade, is not yet widespread. Interleukin-1 (IL-1) is an abundant cytokine in tumor sites and it controls the inflammatory pro-invasive and immunosuppressive nature of the microenvironment. If activates the microenvironment and also affects the malignant cells. We have studies how the secreted form of IL-1, i.e., IL-1b affects the microenvironments of primary breast tumors and lung metastases and whether its neutralization will affect invasiveness.

Materials and Methods- We have used the model of murine 4T1 breast cancer cells, which represents the equivalent of human triple negative breast cancer (TNBC). Upon orthotopic injection of 4T1 cells, local primary tumors develop followed by spontaneous metastasis to the lungs.

Results and Discussion- In wild-type (WT) mice, progressive tumors developed and induced spontaneous lung metastasis, while in IL-1b knockout (KO) mice, we observed initial tumor growth followed by regression, no formation of lung metastases and development of resistance to a challenge with the malignant cells. We further studied the role of microenvironment IL-1b on inflammation/immunity, emphasizing early events (days 10-14 after inoculation), which are critical for the outcome of the malignant process. In WT mice, early IL-1b-induced and CCL2-mediated recruitment of inflammatory monocytes was potent, however, impaired in IL-1b KO mice. Also, IL-1b-induced in-situ differentiation of inflammatory monocytes into IL-10-secreting immunosuppressive TAMs, by CSF-1 and other mediators, was potent in WT mice and marginal in in IL-1b KO mice. The relative abundance of inflammatory monocyte-derived IL-12 producing DCs was much higher in tumor sites in IL-1b KO mice, as compared to WT mice. In IL-1b KO mice, activated CD8⁺ in tumor cell deposits were abundant and resulted in its regression. IL-1b neutralization induced only partial anti-tumor effects, but its combination with anti-PD-1 antibodies, completely inhibited tumor growth. In WT mice with large tumors, in which the primary tumor was resected, and were subsequently treated with anti-IL-1b and anti-PD-1 antibodies, lung metastasis was significantly reduced.

Conclusion- Treatment of minimal residual disease (MRD), after tumor debulkment, enables targeting of the microenvironment, also with anti-IL-1b anti-PD-1 antibodies, can be effective for the prevention of tumor recurrence and metastasis.