{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,28]],"date-time":"2026-10-28T05:47:27Z","timestamp":1793166447124,"version":"4.5.0"},"reference-count":45,"publisher":"BMJ","issue":"11","license":[{"start":{"date-parts":[[2024,11,29]],"date-time":"2024-11-29T00:00:00Z","timestamp":1732838400000},"content-version":"unspecified","delay-in-days":28,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"name":"Taishan Scholarship","award":["tsqn202312362"],"award-info":[{"award-number":["tsqn202312362"]}]},{"DOI":"10.13039\/501100004735","name":"Natural Science Foundation of Hunan Province","doi-asserted-by":"publisher","award":["2021JJ31061"],"award-info":[{"award-number":["2021JJ31061"]}],"id":[{"id":"10.13039\/501100004735","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004735","name":"Natural Science Foundation of Hunan Province","doi-asserted-by":"publisher","award":["2022JJ70165"],"award-info":[{"award-number":["2022JJ70165"]}],"id":[{"id":"10.13039\/501100004735","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81530084"],"award-info":[{"award-number":["81530084"]}],"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":["81974465"],"award-info":[{"award-number":["81974465"]}],"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":["82030087"],"award-info":[{"award-number":["82030087"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002858","name":"Postdoctoral Science Foundation","doi-asserted-by":"crossref","award":["2020M672523"],"award-info":[{"award-number":["2020M672523"]}],"id":[{"id":"10.13039\/501100002858","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100002858","name":"Postdoctoral Science Foundation","doi-asserted-by":"crossref","award":["2021T140747"],"award-info":[{"award-number":["2021T140747"]}],"id":[{"id":"10.13039\/501100002858","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["J Immunother Cancer"],"accepted":{"date-parts":[[2024,11,5]]},"published-print":{"date-parts":[[2024,11]]},"abstract":"<jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>Programmed death-1 (PD-1) checkpoint blockade has revolutionized cancer therapy, yet its clinical success is confined to a subset of patients, underscoring the urgent need to understand the molecular underpinnings of programmed cell death ligand 1 (PD-L1) expression to combat immunotherapy resistance.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>Employing CRISPR\/Cas9 screening, we identified key regulators of PD-L1 in non-small cell lung cancer (NSCLC) cells, focusing on the transcription factor CEBPB and its isoform liver-enriched inhibitory protein (LIP). Through chromatin immunoprecipitation (ChIP) and luciferase reporter assays, we explored the interaction between LIP and basic-helix-loop-helix E22 (BHLHE22) in controlling PD-L1 transcription. We also used immunofluorescence and NBD-CI assays to examine how N-terminal acetylation affects LIP\u2019s subcellular localization. The impact of LIP on tumor growth was assessed via subcutaneous tumorigenicity assays, while immunohistochemistry and immunofluorescence were used to analyze LIP-induced alterations in the tumor immune microenvironment.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>Our research indicates that CEBPB, particularly its LIP isoform, significantly suppresses PD-L1 expression in NSCLC cells. This suppression is contingent on LIP\u2019s N-terminal acetylation by the N-terminal acetyltransferase A complex, which facilitates LIP\u2019s nuclear entry and interaction with BHLHE22. This interaction leads to the formation of a co-repressor complex at the PD-L1 promoter, effectively reducing PD-L1 expression and enhancing the tumor immune response.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>Identifying CEBPB, especially the LIP isoform, as a pivotal regulator of PD-L1 expression sheds light on the mechanisms behind PD-1 blockade resistance in NSCLC. Our findings suggest that modulating LIP\u2019s function or its molecular interactions might offer a novel approach to boosting the efficacy of immunotherapies.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1136\/jitc-2024-009905","type":"journal-article","created":{"date-parts":[[2024,11,29]],"date-time":"2024-11-29T23:55:17Z","timestamp":1732924517000},"page":"e009905","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":6,"title":["N-terminal acetylation of transcription factor LIP induces immune therapy resistance via suppression of PD-L1 expression in non-small cell lung cancer"],"prefix":"10.1136","volume":"12","author":[{"given":"Xiang","family":"He","sequence":"first","affiliation":[{"name":"Key Laboratory of Molecular Radiation Oncology Hunan Province, Xiangya Cancer Center, Xiangya Hospital Central South University, Changsha, China"},{"name":"National Clinical Research Center for Geriatric Disorders, Xiangya Hospital 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