The use of anti-IL-1β together with anti-PD-1 to treat a minimal residual disease of breast cancer

To probe the role of microenvironment IL-1b in the balance between inflammation and immunity in the tumor microenvironment, we used the model of orthotopically injected 4T1 breast cancer cells into IL-1b deficient (IL-1β KO) and wild-type (WT). In WT mice tumor progressed and induced lung metastases, while in IL-1β KO mice tumors started to regress after 14 days. Tumor regression in IL-1β KO mice is CD8⁺ T cell dependent, while in the microenvironment of tumors in WT mice inflammatory monocytes differentiated into IL-10 immunosuppressive TAMs, which induced progression. Based on the results, we have developed a novel immunotherapeutic approach to target the pro-inflammatory and immunosuppressive nature of the tumor microenvironment, which will also enable the development of anti-tumor cell immunity. Thus, to target the tumor microenvironment, we have used antibodies that neutralize two distinct targets, i.e., anti-IL-1β and anti-PD-1. In addition to the synergy between these agents, anti-IL-1β antibodies has potential to ablate the inflammatory effects that anti-PD-1 induces in patients. In early breast tumors, in WT mice, this combinatorial treatment leads to inhibition in tumor development. In late, breast cancer tumors, the local tumor was initially excised and then a protocol of treatment of anti-IL-1β and anti-PD-1 was applied, which lead to an increased significant survival of metastasis-free mice, as compared to only resected mice or mice treated with a single agent. Overall, our results to target in cancer patients conventional first-line therapies, to deplete the malignant cells, and then target the microenvironment to prevent tumor recurrence and metastasis.