Blocking IL-1β reverses the immunosuppression in mouse breast cancer and synergizes with anti–PD-1 for tumor abrogation

Abstract

Interleukin-1β (IL-1β) is abundant in the tumor microenvironment, where this cytokine can promote tumor growth, but also antitumor activities. We studied IL-1β during early tumor progression using a model of orthotopically introduced 4T1 breast cancer cells. Whereas there is tumor progression and spontaneous metastasis in wild-type (WT) mice, in IL-1β–deficient mice, tumors begin to grow but subsequently regress. This change is due to recruitment and differentiation of inflammatory monocytes in the tumor microenvironment. In WT mice, macrophages heavily infiltrate tumors, but in IL-1β–deficient mice, low levels of the chemokine CCL2 hamper recruitment of monocytes and, together with low levels of colony-stimulating factor-1 (CSF-1), inhibit their differentiation into macrophages. The low levels of macrophages in IL-1β–deficient mice result in a relatively high percentage of CD11b+ dendritic cells (DCs) in the tumors. In WT mice, IL-10 secretion from macrophages is dominant and induces immunosuppression and tumor progression; in contrast, in IL-1β–deficient mice, IL-12 secretion by CD11b+ DCs prevails and supports antitumor immunity. The antitumor immunity in IL-1β–deficient mice includes activated CD8+ lymphocytes expressing IFN-γ, TNF-α, and granzyme B; these cells infiltrate tumors and induce regression. WT mice with 4T1 tumors were treated with either anti–IL-1β or anti–PD-1 Abs, each of which resulted in partial growth inhibition. However, treating mice first with anti–IL-1β Abs followed by anti–PD-1 Abs completely abrogated tumor progression. These data define microenvironmental IL-1β as a master cytokine in tumor progression. In addition to reducing tumor progression, blocking IL-1β facilitates checkpoint inhibition.

Uric Acid Has Direct Proinflammatory Effects on Human Macrophages by Increasing Proinflammatory Mediators and Bacterial Phagocytosis Probably via URAT1

“…We found that uric acid stimulates TNF-alpha production, but not IL-1 beta, in a dose-dependent fashion after confirming that human monocytes were properly differentiated into macrophages using a strategy that combined cell size and complexity as well CD14 expression. TNF-alpha and IL-1 beta are proinflammatory cytokines that play key roles in fever, cachexia, tumorigenesis inhibition, pyroptosis-related cell death, and immune cell recruitment [24][25][26]. However, TNF-alpha, but not IL-1 beta, has been consistently associated with increased serum levels of uric acid in several pathologic scenarios.…”

Interleukin-1 and Related Cytokines in the Regulation of Inflammation and Immunity

“…IL-1-mediated tumor promotion has been identified in different murine and human tumor types, including sarcomas, melanoma, pancreatic ductal adenocarcinoma (Ling et al, 2012;Melisi et al, 2009;Tjomsland et al, 2013;Zhuang et al, 2016), myelomas (Lust et al, 2016), and breast carcinomas and involves different mechanisms ( Figure 4A). IL-1 has been shown to sustain the expansion and immunosuppressive function of myeloid cells in tumor-bearing mice (Elkabets et al, 2010;Kaplanov et al, 2019;Pan et al, 2017).…”

Myeloid-derived suppressor cell subsets drive glioblastoma growth in a sex-specific manner

“…We leveraged these distinct gene expression signatures associate with suppression of the antitumor immune response to identify drug candidates that could be repurposed for cancer immunotherapy. Although, IL-1 is a prototypical pro-inflammatory cytokine, recent studies suggest that IL-1β can drive tumorigenesis by promoting a CSC phenotype, modulating the immune response and inducing tumorigenic edema [39][40][41][42] . Importantly, randomized clinical testing of canakinumab, an anti-IL-1β antibody, pointed out to a reduction in lung cancer incidence of patients with atherosclerosis 43 .…”