Abstract Title:

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

Abstract Source:

Proc Natl Acad Sci U S A. 2018 Dec 13. Epub 2018 Dec 13. PMID: 30545915

Abstract Author(s):

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

Article Affiliation:

Irena Kaplanov


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 spontaneousmetastasis 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 CD11bdendritic 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 CD11bDCs prevails and supports antitumor immunity. The antitumor immunity in IL-1β-deficient mice includes activated CD8lymphocytes 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 completelyabrogated 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.

Study Type : Animal Study

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