Gong and Li et al. demonstrated that tissue-specific neutrophils in lungs expressed immunosuppressive factors in both naive and tumor-bearing mice and humans. Lung mesenchymal cell-derived soluble factor prostaglandin E2 (PGE2) reprogrammed infiltrating neutrophils to be immunosuppressive, which was further enhanced by the host neutrophilic inflammation. Genetic or pharmacological inhibition of PGE2 signaling reduced the immunosuppressive capacity of lung neutrophils, mitigated lung metastasis of breast cancer in vivo, and improved the therapeutic efficacy of adoptive T cell therapy in treating lung metastasis.
ABSTRACT: 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 environment. 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 immunosuppressive 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 synthase 2 (PTGS2), the rate-limiting enzyme for prostaglandin E(2) (PGE(2)) biosynthesis. MC-specific deletion of Ptgs2 or pharmacological inhibition of PGE(2) receptors reversed lung neutrophil-mediated immunosuppression and mitigated lung metastasis of breast cancer in vivo. These lung stroma-targeting strategies substantially improved 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.
Author Info: (1) Jackson Laboratory, Bar Harbor, ME 04609, USA. (2) Jackson Laboratory, Bar Harbor, ME 04609, USA. (3) Jackson Laboratory, Bar Harbor, ME 04609, USA. (4) Jackson Laboratory, Bar
Author Info: (1) Jackson Laboratory, Bar Harbor, ME 04609, USA. (2) Jackson Laboratory, Bar Harbor, ME 04609, USA. (3) Jackson Laboratory, Bar Harbor, ME 04609, USA. (4) Jackson Laboratory, Bar Harbor, ME 04609, USA. (5) Jackson Laboratory, Bar Harbor, ME 04609, USA. (6) Jackson Laboratory, Bar Harbor, ME 04609, USA. (7) Jackson Laboratory, Bar Harbor, ME 04609, USA. Tufts University School of Medicine, Boston, MA 02111, USA. Graduate School of Biomedical Sciences and Engineering, University of Maine, Orono, ME 04469, USA.
