{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T04:45:56Z","timestamp":1791521156019,"version":"4.3.4"},"reference-count":70,"publisher":"BMJ","issue":"12","license":[{"start":{"date-parts":[[2024,12,4]],"date-time":"2024-12-04T00:00:00Z","timestamp":1733270400000},"content-version":"unspecified","delay-in-days":3,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/100022963","name":"Key Research and Development Program of Zhejiang Province","doi-asserted-by":"publisher","award":["2022C03105"],"award-info":[{"award-number":["2022C03105"]}],"id":[{"id":"10.13039\/100022963","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82072959"],"award-info":[{"award-number":["82072959"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82273178"],"award-info":[{"award-number":["82273178"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82403805"],"award-info":[{"award-number":["82403805"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100012175","name":"Zhejiang Traditional Chinese Medicine Administration","doi-asserted-by":"publisher","award":["2022ZA095"],"award-info":[{"award-number":["2022ZA095"]}],"id":[{"id":"10.13039\/501100012175","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100012175","name":"Zhejiang Traditional Chinese Medicine Administration","doi-asserted-by":"publisher","award":["2023ZR108"],"award-info":[{"award-number":["2023ZR108"]}],"id":[{"id":"10.13039\/501100012175","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["J Immunother Cancer"],"accepted":{"date-parts":[[2024,11,15]]},"published-print":{"date-parts":[[2024,12]]},"abstract":"<jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>Lung metastasis remains the primary cause of tumor-related mortality, with limited treatment options and unsatisfactory efficacy. In preclinical studies, T helper 9 (T<jats:sub>H<\/jats:sub>9) cells have shown promise in treating solid tumors. However, it is unclear whether T<jats:sub>H<\/jats:sub>9 cells can tackle more challenging situations, such as established lung metastases. Moreover, comprehensive exploration into the nuanced biological attributes of T<jats:sub>H<\/jats:sub>9 cells is imperative to further unravel their therapeutic potential.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>We adoptively transferred T<jats:sub>H<\/jats:sub>1, T<jats:sub>H<\/jats:sub>9, and T<jats:sub>H<\/jats:sub>17 cells into subcutaneous, <jats:italic>in situ<\/jats:italic>, and established lung metastases models of osteosarcoma and triple-negative breast cancer, respectively, comparing their therapeutic efficacy within each distinct model. We employed flow cytometry and an <jats:italic>in vivo<\/jats:italic> imaging system to evaluate the accumulation patterns of T<jats:sub>H<\/jats:sub>1, T<jats:sub>H<\/jats:sub>9, and T<jats:sub>H<\/jats:sub>17 cells in the lungs after transfusion. We conducted bulk RNA sequencing on <jats:italic>in vitro<\/jats:italic> differentiated T<jats:sub>H<\/jats:sub>9 cells to elucidate the chemokine receptor CXCR4, which governs their heightened pulmonary tropism relative to T<jats:sub>H<\/jats:sub>1 and T<jats:sub>H<\/jats:sub>17 cell counterparts. Using Cd4<jats:sup>\n                        <jats:italic>cre<\/jats:italic>\n                     <\/jats:sup> Cxcr4 <jats:sup>\n                        <jats:italic>flox\/flox<\/jats:italic>\n                     <\/jats:sup> mice, we investigate the effects of CXCR4 on the lung tropism of T<jats:sub>H<\/jats:sub>9 cells. We performed mass spectrometry to identify the E3 ligase responsible for CXCR4 ubiquitination and elucidated the mechanism governing CXCR4 expression within T<jats:sub>H<\/jats:sub>9 cellular milieu. Ultimately, we analyzed the tumor immune composition after T<jats:sub>H<\/jats:sub>9 cell transfusion and evaluated the therapeutic efficacy of adjunctive anti-programmed cell death protein-1 (PD-1) therapy in conjunction with T<jats:sub>H<\/jats:sub>9 cells.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>In this study, we provide evidence that T<jats:sub>H<\/jats:sub>9 cells exhibit higher lung tropism than T<jats:sub>H<\/jats:sub>1 and T<jats:sub>H<\/jats:sub>17 cells, thereby exhibiting exceptional efficacy in combating established lung metastases. CXCR4-CXCL12 axis is responsible for lung tropism of T<jats:sub>H<\/jats:sub>9 cells as ablating CXCR4 in CD4<jats:sup>+<\/jats:sup> T cells reverses their lung accumulation. Mechanistically, tumor necrosis factor receptor-associated factor 6 (TRAF6)-driven hyperactivation of NF-\u03baB signaling in T<jats:sub>H<\/jats:sub>9 cells inhibited ITCH-mediated ubiquitination of CXCR4, resulting in increased CXCR4 accumulation and enhanced lung tropism of T<jats:sub>H<\/jats:sub>9 cells. Besides, T<jats:sub>H<\/jats:sub>9 cells\u2019 transfusion significantly improved the immunosuppressed microenvironment. T<jats:sub>H<\/jats:sub>9 cells and anti-PD-1 exhibit synergistic effects in tumor control.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>Our findings emphasized the innate lung tropism of T<jats:sub>H<\/jats:sub>9 cells driven by the activation of TRAF6, which supports the potential of T<jats:sub>H<\/jats:sub>9 cells as a promising therapy for established lung metastases.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1136\/jitc-2024-009629","type":"journal-article","created":{"date-parts":[[2024,12,4]],"date-time":"2024-12-04T20:40:37Z","timestamp":1733344837000},"page":"e009629","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":7,"title":["Natural lung-tropic T<sub>H<\/sub>9 cells: a sharp weapon for established lung 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Medicine in Universities of Shandong, Jinan Clinical Research Center for Respiratory Disease, Jinan, Shandong, People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eloy","family":"Yinwang","sequence":"additional","affiliation":[{"name":"Department of Orthopedics, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang, People's Republic of China"},{"name":"Orthopaedic Research Institute, Zhejiang University, Hangzhou, Zhejiang, People's Republic of China"},{"name":"Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang Province, Hangzhou, Zhejiang, People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shengdong","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Orthopedics, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang, People's Republic of China"},{"name":"Orthopaedic 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