Integrin-dependent neutrophil slowing reduces lung perfusion and supports metastasis in a model of breast cancer.

Abstract

Neutrophils are critical in establishing a tumor-cell-nurturing and immunosuppressive pulmonary "pre-metastatic" niche in breast cancer. The localization and behavior of these neutrophils is, however, not well described. Using multiplexed imaging to investigate the pre-metastatic lung in a spontaneously metastatic mammary cancer model, we uncover that neutrophils with impaired intravascular motility congest the capillaries of pre-metastatic lungs. Slowed neutrophil transit is reversed by activating βintegrin with an antibody and can be recapitulated by treating non-tumor-bearing mice with G-CSF. Neutrophil congestion causes a reduction of intravenously injected microbeads in the lung, suggestive of lower perfusion. In a model where tumor cells are injected intravenously into mammary-cancer-bearing Rag1-deficient mice, we observe lower lung experimental metastasis burdens after activating βintegrins. Overall, our study proposes that integrin-mediated neutrophil congestion of the alveolar capillaries contributes to the pulmonary pre-metastatic niche.