Immunosuppressive macrophages determine the effect of cellular senescence on tumor progression.

Abstract

Cells terminally arrested in the cell cycle that exhibit a distinct secretory phenotype are referred to as senescent. These cells play a complex role during tumor progression; they can inhibit or promote tumor growth depending on disease stage. We developed a mouse model that allows monitoring and selective elimination of cells expressing high levels of the cyclin-dependent kinase inhibitor p16 and interleukin-6. These mice, termed SuSe (suicidal senescence), were crossed with the mouse mammary tumor virus-polyomavirus middle T antigen (MMTV-PyMT) model of breast cancer. Functional characterization in SuSe/PyMT mice confirmed that depletion of senescent cells (senolysis) in early and late lesions accelerated and decelerated tumor growth and metastasis, respectively. Tumor acceleration was attributed to expansion of immunosuppressive, protumorigenic macrophages. C-C motif chemokine ligand 2 was identified as an autocrine chemokine essential for their recruitment and maintenance. Depletion of these macrophages reversed the effects of senescent cell clearance, rendering senolysis antitumorigenic even at early stages. Our results suggest that targeting immunosuppressive macrophages can preserve the benefits of senolysis while mitigating adverse effects.