{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,7]],"date-time":"2026-11-07T10:54:48Z","timestamp":1794048888306,"version":"4.8.0"},"reference-count":47,"publisher":"Oxford University Press (OUP)","issue":"6","license":[{"start":{"date-parts":[[2018,12,1]],"date-time":"2018-12-01T00:00:00Z","timestamp":1543622400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2018,12,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Pulmonary lymphangioleiomyomatosis (LAM) is a slow-progressing metastatic disease that is driven by mutations in the tumor suppressor tuberous sclerosis complex 1\/2 (TSC1\/2). Rapamycin inhibits LAM cell proliferation and is the only approved treatment, but it cannot cause the regression of existing lesions and can only stabilize the disease. However, in other cancers, immunotherapies such as checkpoint blockade against PD-1 and its ligand PD-L1 have shown promise in causing tumor regression and even curing some patients. Thus, we asked whether PD-L1 has a role in LAM progression. In vitro, PD-L1 expression in murine Tsc2-null cells is unaffected by mTOR inhibition with torin but can be upregulated by IFN-\u03b3. Using immunohistochemistry and single-cell flow cytometry, we found increased PD-L1 expression both in human lung tissue from patients with LAM and in Tsc2-null lesions in a murine model of LAM. In this model, PD-L1 is highly expressed in the lung by antigen-presenting and stromal cells, and activated T cells expressing PD-1 infiltrate the affected lung. In vivo treatment with anti\u2013PD-1 antibody significantly prolongs mouse survival in the model of LAM. Together, these data demonstrate that PD-1\/PD-L1\u2013mediated immunosuppression may occur in LAM, and suggest new opportunities for therapeutic targeting that may provide benefits beyond those of rapamycin.<\/jats:p>","DOI":"10.1165\/rcmb.2018-0123oc","type":"journal-article","created":{"date-parts":[[2018,8,10]],"date-time":"2018-08-10T15:49:35Z","timestamp":1533916175000},"page":"723-732","source":"Crossref","is-referenced-by-count":56,"title":["Immune Checkpoint Ligand PD-L1 Is Upregulated in Pulmonary Lymphangioleiomyomatosis"],"prefix":"10.1093","volume":"59","author":[{"given":"Katharina","family":"Maisel","sequence":"first","affiliation":[{"name":"Institute for Molecular Engineering, University of Chicago, Chicago, Illinois"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mervyn J.","family":"Merrilees","sequence":"additional","affiliation":[{"name":"Department of Anatomy and Medical Imaging, School of Medical Sciences, University of Auckland, Auckland, New Zealand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elena N.","family":"Atochina-Vasserman","sequence":"additional","affiliation":[{"name":"Penn Center for Pulmonary Biology, Pulmonary, Allergy and Critical Care Division, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lurong","family":"Lian","sequence":"additional","affiliation":[{"name":"Penn Center for Pulmonary Biology, Pulmonary, Allergy and Critical Care Division, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kseniya","family":"Obraztsova","sequence":"additional","affiliation":[{"name":"Penn Center for Pulmonary Biology, Pulmonary, Allergy and Critical Care Division, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryan","family":"Rue","sequence":"additional","affiliation":[{"name":"Penn Center for Pulmonary Biology, Pulmonary, Allergy and Critical Care Division, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander N.","family":"Vasserman","sequence":"additional","affiliation":[{"name":"Penn Center for Pulmonary Biology, Pulmonary, Allergy and Critical Care Division, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ning","family":"Zuo","sequence":"additional","affiliation":[{"name":"Department of Anatomy and Medical Imaging, School of Medical Sciences, University of Auckland, Auckland, New Zealand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luis F.","family":"Angel","sequence":"additional","affiliation":[{"name":"New York University Langone Medical Center, New York, New York"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew J.","family":"Gow","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, New Jersey; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Inkyung","family":"Kang","sequence":"additional","affiliation":[{"name":"Matrix Biology Program, Benaroya Research Institute, Seattle, Washington"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas N.","family":"Wight","sequence":"additional","affiliation":[{"name":"Matrix Biology Program, Benaroya Research Institute, Seattle, Washington"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Evgeniy","family":"Eruslanov","sequence":"additional","affiliation":[{"name":"Department of Surgery, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melody A.","family":"Swartz","sequence":"additional","affiliation":[{"name":"Institute for Molecular Engineering, University of Chicago, Chicago, Illinois"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vera P.","family":"Krymskaya","sequence":"additional","affiliation":[{"name":"Penn Center for Pulmonary Biology, Pulmonary, Allergy and Critical Care Division, and"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2018,12,1]]},"reference":[{"key":"2026012222052754000_bib1","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1146\/annurev-med-050715-104245","article-title":"Lymphangioleiomyomatosis: a monogenic model of malignancy","volume":"68","author":"Krymskaya","year":"2017","journal-title":"Annu Rev Med"},{"key":"2026012222052754000_bib2","doi-asserted-by":"crossref","first-page":"6085","DOI":"10.1073\/pnas.97.11.6085","article-title":"Mutations in the tuberous sclerosis complex gene TSC2 are a cause of sporadic pulmonary lymphangioleiomyomatosis","volume":"97","author":"Carsillo","year":"2000","journal-title":"Proc Natl Acad Sci USA"},{"key":"2026012222052754000_bib3","doi-asserted-by":"crossref","first-page":"30958","DOI":"10.1074\/jbc.M202678200","article-title":"Tuberin regulates p70 S6 kinase activation and ribosomal protein S6 phosphorylation. 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