Macrophages facilitate tumor cell PD-L1 expression via an IL-1 beta-centered loop to attenuate immune checkpoint blockade

Tumor-associated macrophages (TAMs) play critical roles in reprogramming other immune cells and orchestrating antitumor immunity. However, the interplay between TAMs and tumor cells responsible for enhancing immune evasion remains insufficiently understood. Here, we revealed that interleukin (IL)-1 beta was among the most abundant cytokines within the in vitro tumor-macrophage coculture system, and enhanced IL-1 beta expression was associated with impaired cytotoxicity of CD8(+) T cells in human ovarian cancer, indicating the possibility that IL-1 beta mediated immunosuppression during tumor-TAMs crosstalk. Mechanistically, we demonstrated that IL-1 beta significantly boosted programmed death-ligand 1 (PD-L1) expression in tumor cells via the activation of the nuclear factor-kappa b signaling cascade. Specifically, IL-1 beta released from TAMs was triggered by lactate, the anaerobic metabolite of tumor cells, in an inflammasome activation-dependent manner. IL-1 beta sustained and intensified immunosuppression by promoting C-C motif chemokine ligand 2 secretion in tumor cells to fuel TAMs recruitment. Importantly, IL-1 beta neutralizing antibody significantly curbed tumor growth and displayed synergistic antitumor efficacies with antiPD-L1 antibody in tumor-bearing mousemodels. Together, this study presents an IL-1 beta-centered immunosuppressive loop between TAMs and tumor cells, highlighting IL-1 beta as a candidate therapeutic target to reverse immunosuppression and potentiate immune checkpoint blockade.