{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T06:45:21Z","timestamp":1790232321529,"version":"4.1.0"},"reference-count":73,"publisher":"American Society for Clinical Investigation","issue":"8","funder":[{"name":"U.S. Department of Defense","award":["TS160057"],"award-info":[{"award-number":["TS160057"]}]},{"name":"Tuberous Sclerosis Alliance","award":["2016D006584"],"award-info":[{"award-number":["2016D006584"]}]},{"name":"Engles Program for TSC and LAM Research","award":["private"],"award-info":[{"award-number":["private"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2018,4,19]]},"abstract":"<jats:p>\n                    Tuberous sclerosis complex (TSC) is an incurable multisystem disease characterized by mTORC1-hyperactive tumors. TSC1\/2 mutations also occur in other neoplastic disorders, including lymphangioleiomyomatosis (LAM) and bladder cancer. Whether TSC-associated tumors will respond to immunotherapy is unknown. We report here that the programmed death 1 coinhibitory receptor (PD-1) is upregulated on T cells in renal angiomyolipomas (AML) and pulmonary lymphangioleiomyomatosis (LAM). In C57BL\/6J mice injected with syngeneic TSC2-deficient cells, anti\u2013PD-1 alone decreased 105K tumor growth by 67% (\n                    <jats:italic>P<\/jats:italic>\n                    &lt; 0.0001); the combination of PD-1 and CTLA-4 blockade was even more effective in suppressing tumor growth. Anti\u2013PD-1 induced complete rejection of TSC2-deficient 105K tumors in 37% of mice (\n                    <jats:italic>P<\/jats:italic>\n                    &lt; 0.05). Double blockade of PD-1 and CTLA-4 induced rejection in 62% of mice (\n                    <jats:italic>P<\/jats:italic>\n                    &lt; 0.01). TSC2 reexpression in TSC2-deficient TMKOC cells enhanced antitumor immunity by increasing T cell infiltration and production of IFN-\u03b3\/TNF-\u03b1 by T cells, suggesting that TSC2 and mTORC1 play specific roles in the induction of antitumor immunity. Finally, 1 month of anti\u2013PD-1 blockade reduced renal tumor burden by 53% (\n                    <jats:italic>P<\/jats:italic>\n                    &lt; 0.01) in genetically engineered\n                    <jats:italic>\n                      Tsc2\n                      <jats:sup>+\/\u2013<\/jats:sup>\n                    <\/jats:italic>\n                    mice. Taken together, these data demonstrate for the first time to our knowledge that checkpoint blockade may have clinical efficacy for TSC and LAM, and possibly other benign tumor syndromes, potentially yielding complete and durable clinical responses.\n                  <\/jats:p>","DOI":"10.1172\/jci.insight.98674","type":"journal-article","created":{"date-parts":[[2018,4,18]],"date-time":"2018-04-18T11:02:49Z","timestamp":1524049369000},"source":"Crossref","is-referenced-by-count":72,"title":["TSC2-deficient tumors have evidence of T cell exhaustion and respond to anti\u2013PD-1\/anti\u2013CTLA-4 immunotherapy"],"prefix":"10.1172","volume":"3","author":[{"given":"Heng-Jia","family":"Liu","sequence":"first","affiliation":[{"name":"Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women\u2019s Hospital, Harvard Medical School, Boston, Massachusetts, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrick H.","family":"Lizotte","sequence":"additional","affiliation":[{"name":"Belfer Center for Applied Cancer Science, Boston, Massachusetts, USA."},{"name":"Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heng","family":"Du","sequence":"additional","affiliation":[{"name":"Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women\u2019s Hospital, Harvard Medical School, Boston, Massachusetts, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria C.","family":"Speranza","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA."},{"name":"Harvard Medical School, Boston, Massachusetts, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hilaire C.","family":"Lam","sequence":"additional","affiliation":[{"name":"Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women\u2019s Hospital, Harvard Medical School, Boston, Massachusetts, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1662-2982","authenticated-orcid":true,"given":"Spencer","family":"Vaughan","sequence":"additional","affiliation":[{"name":"Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women\u2019s Hospital, Harvard Medical School, Boston, Massachusetts, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicola","family":"Alesi","sequence":"additional","affiliation":[{"name":"Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women\u2019s Hospital, Harvard Medical School, Boston, Massachusetts, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kwok-Kin","family":"Wong","sequence":"additional","affiliation":[{"name":"Belfer Center for Applied Cancer Science, Boston, Massachusetts, USA."},{"name":"Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA."},{"name":"Harvard Medical School, Boston, Massachusetts, USA."},{"name":"Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA."},{"name":"Laura and Isaac Perlmutter Cancer Center, New York University Langone Medical Center, New York, New York, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gordon J.","family":"Freeman","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA."},{"name":"Harvard Medical School, Boston, Massachusetts, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arlene H.","family":"Sharpe","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunobiology, Harvard Medical School, Boston, Massachusetts, USA."},{"name":"Evergrande Center for Immunologic Diseases, Brigham and Women\u2019s Hospital, Harvard 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