{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,29]],"date-time":"2026-10-29T00:15:44Z","timestamp":1793232944922,"version":"4.5.0"},"reference-count":74,"publisher":"Oxford University Press (OUP)","issue":"6","license":[{"start":{"date-parts":[[2025,1,22]],"date-time":"2025-01-22T00:00:00Z","timestamp":1737504000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"DOI":"10.13039\/100000005","name":"Department of Defense","doi-asserted-by":"publisher","award":["W81XWH-19-1-0517"],"award-info":[{"award-number":["W81XWH-19-1-0517"]}],"id":[{"id":"10.13039\/100000005","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Japan Society for the Promotion of Science Grains-in-Aid for Scientific Research","award":["JP23K19510"],"award-info":[{"award-number":["JP23K19510"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,6,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Immune checkpoint inhibitors have shown clinical benefit in non\u2013small cell lung cancer\u2013derived brain metastasis, but their efficacy in lung-to-leptomeningeal brain metastasis remains poor.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>A pair-matched RNA expression dataset of patients with non\u2013small cell lung cancer and brain metastases was analyzed to identify brain metastasis\u2013specific suppressive tumor microenvironment features. Next, we created immune-competent lung-to-leptomeningeal brain metastasis mouse models that mimic clinical lung-to-leptomeningeal brain metastasis. We evaluated the efficacy of intrathecal delivery of allogeneic stem cells engineered to release single-chain variable part of the antigen-binding fragment (scFv) anti\u2013programmed cell death 1 protein (PD-1). To enhance tumor cell killing and subsequent modulation of the immune tumor microenvironment, we explored the therapeutic activity of dual stem cells releasing oncolytic herpes simplex virus (oHSV) and scFvPD-1 and profiled immune and metabolic consequences.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>RNA sequencing analysis of primary non\u2013small cell lung cancer and brain metastases revealed an immune-suppressive tumor microenvironment with reduced immune cells and increased PD-1\u2013positive T cells in brain metastases. We showed decreased immune cells and increased PD-1\u2013positive T cells in the tumor microenvironment of lung-to-leptomeningeal brain metastases compared with primary non-small cell lung cancer in lung-to-leptomeningeal brain metastasis mouse models. Next, we showed that locoregional intrathecal treatment with stem cells releasing scFvPD-1 but not conventional systemic injection of anti\u2013PD-1 antibodies suppressed tumor growth and improved survival in our immune-competent lung-to-leptomeningeal brain metastasis models. Furthermore, dual\u2013stem cells releasing oHSV and scFvPD-1 enhanced therapeutic outcomes by inducing oHSV\u2013mediated immunogenic cell death, activating antitumor T-cell signaling, and disrupting oxidative phosphorylation, all of which sensitized tumors to cisplatin.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Locoregional delivery of dual\u2013stem cells releasing oHSV\/scFvPD-1 effectively targets the immune-suppressive tumor microenvironment in lung-to-leptomeningeal brain metastasis, providing a promising strategy for treating lung-to-leptomeningeal brain metastases.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1093\/jnci\/djaf006","type":"journal-article","created":{"date-parts":[[2025,1,8]],"date-time":"2025-01-08T23:19:40Z","timestamp":1736378380000},"page":"1151-1165","source":"Crossref","is-referenced-by-count":14,"title":["Engineered allogeneic stem cells orchestrate T lymphocyte\u2013driven immunotherapy in immunosuppressive leptomeningeal brain metastasis"],"prefix":"10.1093","volume":"117","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0427-4426","authenticated-orcid":false,"given":"Nobuhiko","family":"Kanaya","sequence":"first","affiliation":[{"name":"Center for Stem Cell and Translational Immunotherapy, Brigham and Women\u2019s Hospital, Harvard Medical School , Boston, MA 02115,","place":["United States"]},{"name":"Department of Neurosurgery, Brigham and Women\u2019s Hospital, Harvard Medical School , Boston, MA 02115,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2756-029X","authenticated-orcid":false,"given":"Waleed","family":"Seddiq","sequence":"additional","affiliation":[{"name":"Center for Stem Cell and Translational Immunotherapy, Brigham and Women\u2019s Hospital, Harvard Medical School , Boston, MA 02115,","place":["United 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Neurosurgery, Brigham and Women\u2019s Hospital, Harvard Medical School , Boston, MA 02115,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3900-1388","authenticated-orcid":false,"given":"Lucia","family":"Moreno Lama","sequence":"additional","affiliation":[{"name":"Center for Stem Cell and Translational Immunotherapy, Brigham and Women\u2019s Hospital, Harvard Medical School , Boston, MA 02115,","place":["United States"]},{"name":"Department of Neurosurgery, Brigham and Women\u2019s Hospital, Harvard Medical School , Boston, MA 02115,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5942-1166","authenticated-orcid":false,"given":"Paulo","family":"Borges","sequence":"additional","affiliation":[{"name":"Center for Stem Cell and Translational Immunotherapy, Brigham and Women\u2019s Hospital, Harvard Medical School , Boston, MA 02115,","place":["United States"]},{"name":"Department of Neurosurgery, Brigham and Women\u2019s Hospital, Harvard Medical School , Boston, MA 02115,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4484-1253","authenticated-orcid":false,"given":"Shinji","family":"Kuroda","sequence":"additional","affiliation":[{"name":"Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences , Okayama 700-8558,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8225-241X","authenticated-orcid":false,"given":"Hiroaki","family":"Wakimoto","sequence":"additional","affiliation":[{"name":"Center for Stem Cell and Translational Immunotherapy, Brigham and Women\u2019s Hospital, Harvard Medical School , Boston, MA 02115,","place":["United States"]},{"name":"Department of Neurosurgery, Brigham and 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