{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T19:42:43Z","timestamp":1790797363538,"version":"4.1.0"},"reference-count":63,"publisher":"European Respiratory Society (ERS)","issue":"5","license":[{"start":{"date-parts":[[2025,7,10]],"date-time":"2025-07-10T00:00:00Z","timestamp":1752105600000},"content-version":"am","delay-in-days":0,"URL":"https:\/\/publications.ersnet.org\/user-licence"}],"funder":[{"DOI":"10.13039\/100012019","name":"Fondation du Souffle","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100012019","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100007380","name":"Fondation de l'Avenir pour la Recherche M\u00e9dicale Appliqu\u00e9e","doi-asserted-by":"publisher","award":["FDM202306017195"],"award-info":[{"award-number":["FDM202306017195"]}],"id":[{"id":"10.13039\/100007380","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Lucy Engles Fund for TSC and LAM Research"},{"name":"Mary Jean Stempien, MD and James W Stricker, MD"},{"DOI":"10.13039\/100008322","name":"CSL Behring","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100008322","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["publications.ersnet.org"],"crossmark-restriction":true},"short-container-title":["Eur Respir J"],"accepted":{"date-parts":[[2025,5,27]]},"published-print":{"date-parts":[[2025,11]]},"abstract":"<jats:sec>\n                    <jats:title>Rationale<\/jats:title>\n                    <jats:p>Lymphangioleiomyomatosis (LAM) is a low-grade neoplasm caused by the proliferation of tuberous sclerosis complex (TSC) 1- or TSC2-deficient LAM cells, resulting in progressive cystic lung disease. The currently approved treatment for LAM delays disease progression but the disease recurs if treatment is discontinued. Therefore, new therapeutic targets and\/or strategies are necessary for a cure. Immunosuppressive M2-like macrophages are involved in the progression of various cancers, but their role in the pathophysiology of LAM and as a putative therapeutic target is unknown.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>To identify the different immune cell populations involved in LAM, we generated a single-cell transcriptomic map of pulmonary LAM. Interactions between macrophages and LAM cells were studied using the Visium spatial transcriptomic platform and immunofluorescence staining on human pulmonary LAM specimens. Direct co-culture models were used to characterise the influence of TSC2-deficient cells on macrophage differentiation. The efficacy of targeting M2-like macrophages was assessed in preclinical mouse models of TSC2-deficient subcutaneous tumours treated with RP-182, a synthetic peptide which reprogrammes macrophages towards an antitumour M1-like phenotype.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Single-cell RNA-sequencing analysis revealed that the majority of macrophages in pulmonary LAM display immunosuppressive markers, including\n                      <jats:italic>CD206\/MRC1<\/jats:italic>\n                      and\n                      <jats:italic>CD163<\/jats:italic>\n                      . Spatial transcriptomic and immunofluorescence analyses showed that M2 macrophages are in close proximity to LAM cells and that LAM cells that are in close proximity to macrophages highly express macrophage-homing factor chemokine ligand\n                      <jats:italic>CXCL12<\/jats:italic>\n                      .\n                      <jats:italic>In vitro<\/jats:italic>\n                      , co-culture of human and mouse macrophages with TSC2-deficient cells resulted in the upregulation of M2-marker-expressing macrophages. Targeting M2 macrophages\n                      <jats:italic>via<\/jats:italic>\n                      treatment with the CD206 modulator RP-182 impaired the growth of TSC2-deficient tumours\n                      <jats:italic>in vivo<\/jats:italic>\n                      .\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      LAM cells recruit and polarise macrophages towards an M2 phenotype. M2-like CD206\n                      <jats:sup>high<\/jats:sup>\n                      macrophages may represent a potential therapeutic target in LAM.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1183\/13993003.00084-2025","type":"journal-article","created":{"date-parts":[[2025,7,10]],"date-time":"2025-07-10T14:40:16Z","timestamp":1752158416000},"page":"2500084","update-policy":"https:\/\/doi.org\/10.1183\/ers-crossmark-policy","source":"Crossref","is-referenced-by-count":9,"title":["Modulation of infiltrating CD206\n                    <sup>+<\/sup>\n                    macrophages restricts progression of pulmonary 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