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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\n                    <jats:sup>+<\/jats:sup>\n                    mesenchymal cells (MCs) and largely via prostaglandin-endoperoxide synthase 2 (PTGS2), the rate-limiting enzyme for prostaglandin E\n                    <jats:sub>2<\/jats:sub>\n                    (PGE\n                    <jats:sub>2<\/jats:sub>\n                    ) biosynthesis. MC-specific deletion of\n                    <jats:italic>Ptgs2<\/jats:italic>\n                    or pharmacological inhibition of PGE\n                    <jats:sub>2<\/jats:sub>\n                    receptors reversed lung neutrophil\u2013mediated immunosuppression and mitigated lung metastasis of breast cancer in vivo. These lung stroma\u2013targeting strategies substantially improved the therapeutic efficacy of adoptive T cell\u2013based 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.\n                  <\/jats:p>","DOI":"10.1126\/sciimmunol.add5204","type":"journal-article","created":{"date-parts":[[2023,2,17]],"date-time":"2023-02-17T13:58:30Z","timestamp":1676642310000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":131,"title":["Immunosuppressive reprogramming of neutrophils by lung mesenchymal cells promotes breast cancer metastasis"],"prefix":"10.1126","volume":"8","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9789-0596","authenticated-orcid":true,"given":"Zheng","family":"Gong","sequence":"first","affiliation":[{"name":"Jackson Laboratory, Bar Harbor, ME 04609, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5360-7234","authenticated-orcid":true,"given":"Qing","family":"Li","sequence":"additional","affiliation":[{"name":"Jackson Laboratory, Bar Harbor, ME 04609, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7970-4785","authenticated-orcid":true,"given":"Jiayuan","family":"Shi","sequence":"additional","affiliation":[{"name":"Jackson Laboratory, Bar Harbor, ME 04609, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6881-396X","authenticated-orcid":true,"given":"Peishan","family":"Li","sequence":"additional","affiliation":[{"name":"Jackson Laboratory, Bar Harbor, ME 04609, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li","family":"Hua","sequence":"additional","affiliation":[{"name":"Jackson Laboratory, Bar Harbor, ME 04609, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4868-1031","authenticated-orcid":true,"given":"Leonard D.","family":"Shultz","sequence":"additional","affiliation":[{"name":"Jackson Laboratory, Bar Harbor, ME 04609, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2436-9593","authenticated-orcid":true,"given":"Guangwen","family":"Ren","sequence":"additional","affiliation":[{"name":"Jackson Laboratory, Bar Harbor, ME 04609, USA."},{"name":"Tufts University School of Medicine, Boston, MA 02111, USA."},{"name":"Graduate School of Biomedical Sciences and Engineering, University of Maine, Orono, ME 04469, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"221","reference":[{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2016.11.037"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature17038"},{"key":"e_1_3_3_4_2","first-page":"2541","article-title":"Temporal progression of metastasis in lung: Cell survival, dormancy, and location dependence of metastatic inefficiency","volume":"60","author":"Cameron M. 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