The Interleukin-1 (IL-1) family is a group of pro-inflammatory and immunoregulatory cytokines that are involved in the malignant process of cancer development. IL-1 is frequently expressed in breast cancer tumors, being produced by the tumor cells themselves or by the tumor microenvironment. However, the exact role played by IL-1 in tumor invasiveness versus anti-tumor immunity is poorly understood. Previously, we have shown that 4T1 malignant tumor cells grow progressively in the fat-pads of wild-type mice and concomitantly induces lung metastasis. However, in IL-1 KO mice, tumors begin to develop but subsequently regressed, due to the induction of a CTL response against the tumor cells. In IL-1 KO mice, no lung metastasis were observed. Our studies show that the presence of IL-1 in the tumor microenvironment in WT mice recruits to the site of the tumor myeloid-derived suppressor cells (MDSCs) and also M2 macrophages, which induce "wound healing" type of inflammation that promotes tumor progression and immune evasion. In contrast, in IL-1KO mice M1 macrophages, which suppress tumor development but can have cytotoxic/cytostatic effects on the tumor cells and additionally serve as antigen-presenting cells (APCs) for the induction of anti-tumor immunity, are detected. Here, we describe in detail the kinetics of myeloid cell accumulation at tumor sites and show that neutralization of IL-1 leads to an attenuation of the MDSC response at the tumor sites.
Taken together, and based on our results, we are in process of designing an efficient IL-1 neutralization system in the tumor microenvironment of WT mice that will mimic the pattern of anti-tumor immunity observed in IL-1 KO mice, leading to tumor regression. These treatments will be applied into mice, after the application of debulking therapies to remove the mass of the primary tumor. This should prevent tumor recurrence and metastasis.
