Immunosuppressive reprogramming of neutrophils by lung mesenchymal cells promotes breast cancer metastasis

Neutrophils, the most abundant innate immune cells, function as crucial regulators of the adaptive immune system in diverse pathological conditions, including metastatic cancer. However, it remains largely unknown whether their immunomodulatory functions are intrinsic or acquired within the pathological tissue environ-ment. Here, using mouse models of metastatic breast cancer in the lungs, we show that, although neutrophils isolated from bone marrow (BM) or blood are minimally immunosuppressive, lung-infiltrating neutrophils are robustly suppressive of both T cells and natural killer (NK) cells. We found that this tissue-specific immunosup-pressive capacity of neutrophils exists in the steady state and is reinforced by tumor-associated inflammation. Acquisition of potent immunosuppression activity by lung-infiltrating neutrophils was endowed by the lung -resident stroma, specifically CD140a+ mesenchymal cells (MCs) and largely via prostaglandin-endoperoxide syn-thase 2 (PTGS2), the rate-limiting enzyme for prostaglandin E2 (PGE2) biosynthesis. MC-specific deletion of Ptgs2 or pharmacological inhibition of PGE2 receptors reversed lung neutrophil-mediated immunosuppression and mitigated lung metastasis of breast cancer in vivo. These lung stroma-targeting strategies substantially im-proved the therapeutic efficacy of adoptive T cell -based immunotherapy in treating metastatic disease in mice. Collectively, our results reveal that the immunoregulatory effects of neutrophils are induced by tissue -resident stroma and that targeting tissue-specific stromal factors represents an effective approach to boost tissue-resident immunity against metastatic disease.