Blocking IL-1β reverses the immunosuppression in mouse breast cancer and synergizes with anti–PD-1 for tumor abrogation
Menée à l'aide de deux modèles murins de cancer mammaire, cette étude met en évidence l'intérêt de bloquer l'interleukine IL-1 bêta pour lever l'immunosuppression tumorale, puis démontre les effets synergiques des anti-IL-1 bêta et des anti-PD1 contre les cellules cancéreuses
Inflammation and immunosuppression are dominant features of cancer progression. In the tumor microenvironment, macrophages produce interleukin-1β (IL-1β), which subsequently recruits myeloid cells from the bone marrow. In mice deficient in IL-1β or in wild-type mice treated with anti–IL-1β Abs, implanted breast cancer tumors regress. Regression is due to decreased tumor-related immunosuppression, meditated mainly by macrophages, and increased antitumor immunity, mediated by elevated dendritic cell function and activated cytotoxic CD8 lymphocytes. Although anti–PD-1 reduces tumor growth, the combination of anti–IL-1β plus anti–PD-1 abrogated the tumors completely. These observations support clinical trials of blocking IL-1β in cancer and that anti–IL-1β is a checkpoint inhibitor.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.