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

Irena Kaplanov, Yaron Carmi, Rachel Kornetsky, Avishai Shemesh, Galina V. Shurin, Michael R. Shurin, Charles A. Dinarello, Elena Voronov, Ron N. Apte

Research output: Contribution to journalArticlepeer-review

145 Scopus citations

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.

Original languageEnglish
Pages (from-to)1361-1369
Number of pages9
JournalProceedings of the National Academy of Sciences of the United States of America
Volume116
Issue number4
DOIs
StatePublished - 22 Jan 2019

Keywords

  • Antitumor immunity
  • Anti–PD-1
  • Breast cancer
  • IL-1β
  • Immunotherapy

ASJC Scopus subject areas

  • General

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