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

Abstract

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)‐1β was among the most abundant cytokines within the in vitro tumor‐macrophage coculture system, and enhanced IL‐1β expression was associated with impaired cytotoxicity of CD8+ T cells in human ovarian cancer, indicating the possibility that IL‐1β mediated immunosuppression during tumor‐TAMs crosstalk. Mechanistically, we demonstrated that IL‐1β significantly boosted programmed death‐ligand 1 (PD‐L1) expression in tumor cells via the activation of the nuclear factor‐κb signaling cascade. Specifically, IL‐1β released from TAMs was triggered by lactate, the anaerobic metabolite of tumor cells, in an inflammasome activation‐dependent manner. IL‐1β sustained and intensified immunosuppression by promoting C‐C motif chemokine ligand 2 secretion in tumor cells to fuel TAMs recruitment. Importantly, IL‐1β neutralizing antibody significantly curbed tumor growth and displayed synergistic antitumor efficacies with anti‐PD‐L1 antibody in tumor‐bearing mouse models. Together, this study presents an IL‐1β‐centered immunosuppressive loop between TAMs and tumor cells, highlighting IL‐1β as a candidate therapeutic target to reverse immunosuppression and potentiate immune checkpoint blockade.

Monocyte derived Galectin-9 and PD-L1 differentially impair innate and adaptive immune response in various phases of chronic HBV infection

“…Additionally, TNF-α-dependent enhancement of Gal-9-expression had been described earlier in primary astrocytes via TNFR1/JNK/c-Jun signalling pathway [19]. Further, the combined IL-4 and TNF-α treatment had been found to cause synergistic augmentation in PD-L1-expression in renal carcinoma cells [20] while the inductive effect of IL-1β on PD-L1 expression had been demonstrated in lung cancer and glioma cell lines [21].…”

Unraveling the Role of the NLRP3 Inflammasome in Lymphoma: Implications in Pathogenesis and Therapeutic Strategies

“…Despite the fact that, in general, NLRP3 inflammasome activation in immune cells exerts antitumor effects, triggering the immune response against cancer cells [35], NLRP3 inflammasome activation in tumor-associated macrophages (TAMs) and the subsequent IL-1β production was shown to promote PD-L1 expression in neoplastic cells via the activation of the NF-κB signaling cascade [189]. Furthermore, IL-1β secretion by TAMs drives an immunosuppressive CD4+ T-cell polarization [190].…”

Development and Validation of a Novel Nomogram Integrated with Hypoxic and Lactate Metabolic Characteristics for Prognosis Prediction in Hepatocellular Carcinoma

“…Increasing evidence suggests that intra-tumoral lactate is a critical regulator that induces the immunosuppressive microenvironment and promotes tumor growth rather than being just a mere metabolic waste. [16][17][18][19] Lactate confers HCC cells with ferroptosis resistance by elevating the levels of antiferroptosis monounsaturated fatty acids and contributes to enhanced proliferation of tumor cells. 20 Intracellular lactate facilitates the proliferation, self-renewal and migration of HCC stem cells by driving the lactylation of H3 histone at K9 and K56.…”