{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T05:07:10Z","timestamp":1788930430239,"version":"build-2803163510"},"reference-count":38,"publisher":"MDPI AG","issue":"17","license":[{"start":{"date-parts":[[2026,9,4]],"date-time":"2026-09-04T00:00:00Z","timestamp":1788480000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Science and Technology Council","award":["112-2320-B-038-047-MY3"],"award-info":[{"award-number":["112-2320-B-038-047-MY3"]}]},{"award":["112-2320-B-038-047-MY3"],"award-info":[{"award-number":["112-2320-B-038-047-MY3"]}],"id":[{"id":"https:\/\/ror.org\/02kv4zf79","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>While the chaperonin-containing TCP-1 (CCT) complex is essential for proteostasis, the distinct roles of individual subunits in tumor immune regulation remain unclear. Here, we identify CCT7 as a previously unrecognized regulator of immune evasion in lung adenocarcinoma (LUAD). Integrative analyses of TCGA and GEO cohorts revealed that CCT7 is markedly upregulated in LUAD and is associated with poor patient prognosis. Functional studies demonstrated that CCT7 knockdown inhibited tumor cell proliferation and migration and enhanced cisplatin-induced apoptosis, yet paradoxically impaired T-cell activation. Mechanistically, transcriptomic and biochemical analyses revealed that CCT7 depletion activated the DR5\u2013MKK4\u2013JNK\u2013c-Jun signaling cascade, resulting in the transcriptional upregulation of PD-L1. Disruption of DR5 or JNK signaling effectively abrogated PD-L1 induction. In contrast, CCT2 depletion exerted the opposite effect by suppressing the DR5\u2013JNK\u2013c-Jun\u2013PD-L1 signaling axis and enhancing T-cell activation. Collectively, these findings reveal unexpected functional divergence among TRiC\/CCT subunits and identify the CCT7\u2013DR5\u2013JNK\u2013c-Jun signaling axis as a previously unrecognized mechanism regulating PD-L1-mediated immune evasion, highlighting the potential therapeutic relevance of this signaling axis in LUAD.<\/jats:p>","DOI":"10.3390\/cells15171613","type":"journal-article","created":{"date-parts":[[2026,9,4]],"date-time":"2026-09-04T16:07:32Z","timestamp":1788538052000},"page":"1613","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Differential Modulation of the DR5\u2013JNK\u2013PD-L1 Signaling Axis by TRiC\/CCT Subunits CCT7 and CCT2 Shapes Tumor Immune Evasion in Lung Adenocarcinoma"],"prefix":"10.3390","volume":"15","author":[{"given":"Hsin-Wei","family":"Jen","sequence":"first","affiliation":[{"name":"Translational Medicine Center, Department of Research, Shin Kong Wu Ho-Su Memorial Hospital, Taipei 111, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hsiang-Ling","family":"Ho","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, Taipei Veterans General Hospital, Taipei 112, Taiwan"},{"name":"Department of Biotechnology and Laboratory Science in Medicine, National Yang Ming Chiao Tung University, Taipei 112, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Teh-Ying","family":"Chou","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, Shin Kong Wu Ho-Su Memorial Hospital, Taipei 111, Taiwan"},{"name":"Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,4]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"446","DOI":"10.1038\/nature25183","article-title":"The biology and management of non-small cell lung cancer","volume":"553","author":"Herbst","year":"2018","journal-title":"Nature"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"584","DOI":"10.1016\/S0025-6196(11)60735-0","article-title":"Non-small cell lung cancer: Epidemiology, risk factors, treatment, and survivorship","volume":"83","author":"Molina","year":"2008","journal-title":"Mayo Clin. Proc."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"299","DOI":"10.1016\/S0140-6736(16)30958-8","article-title":"Lung cancer: Current therapies and new targeted treatments","volume":"389","author":"Hirsch","year":"2017","journal-title":"Lancet"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"136","DOI":"10.1186\/s40364-024-00686-7","article-title":"New strategies for lung cancer diagnosis and treatment: Applications and advances in nanotechnology","volume":"12","author":"Feng","year":"2024","journal-title":"Biomark. Res."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"586","DOI":"10.1200\/JCO.21.01497","article-title":"First-Line Immunotherapy for Non-Small-Cell Lung Cancer","volume":"40","author":"Reck","year":"2022","journal-title":"J. Clin. Oncol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1623","DOI":"10.1016\/j.mayocp.2019.01.013","article-title":"Non-Small Cell Lung Cancer: Epidemiology, Screening, Diagnosis, and Treatment","volume":"94","author":"Duma","year":"2019","journal-title":"Mayo Clin. Proc."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1823","DOI":"10.1056\/NEJMoa1606774","article-title":"Pembrolizumab Versus Chemotherapy for PD-L1-Positive Non-Small-Cell Lung Cancer","volume":"375","author":"Reck","year":"2016","journal-title":"N. Engl. J. Med."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1492","DOI":"10.1093\/annonc\/mdw217","article-title":"Immune escape to PD-L1\/PD-1 blockade: Seven steps to success (or failure)","volume":"27","author":"Kim","year":"2016","journal-title":"Ann. Oncol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"4967","DOI":"10.1073\/pnas.0913774107","article-title":"4.0-\u212b resolution cryo-EM structure of the mammalian chaperonin TRiC\/CCT reveals its unique subunit arrangement","volume":"107","author":"Cong","year":"2010","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"814","DOI":"10.1016\/j.str.2012.03.007","article-title":"The molecular architecture of the eukaryotic chaperonin TRiC\/CCT","volume":"20","author":"Leitner","year":"2012","journal-title":"Structure"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"106","DOI":"10.3892\/ijo.2023.5554","article-title":"A potential tumor marker: Chaperonin containing TCP-1 controls the development of malignant tumors (Review)","volume":"63","author":"Zheng","year":"2023","journal-title":"Int. J. Oncol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"8588","DOI":"10.3748\/wjg.v21.i28.8588","article-title":"Overexpression of chaperonin containing TCP1, subunit 3 predicts poor prognosis in hepatocellular carcinoma","volume":"21","author":"Cui","year":"2015","journal-title":"World J. Gastroenterol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"747","DOI":"10.18632\/aging.203809","article-title":"Overexpression of chaperonin containing TCP1 subunit 7 has diagnostic and prognostic value for hepatocellular carcinoma","volume":"14","author":"Huang","year":"2022","journal-title":"Aging"},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Kasembeli, M., Lau, W.C., Roh, S.H., Eckols, T.K., Frydman, J., Chiu, W., and Tweardy, D.J. (2014). Modulation of STAT3 folding and function by TRiC\/CCT chaperonin. PLoS Biol., 12.","DOI":"10.1371\/journal.pbio.1001844"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"110273","DOI":"10.18632\/oncotarget.22681","article-title":"Targeting chaperonin containing TCP1 (CCT) as a molecular therapeutic for small cell lung cancer","volume":"8","author":"Carr","year":"2017","journal-title":"Oncotarget"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1038\/s41392-020-00278-5","article-title":"TCP1 regulates Wnt7b\/beta-catenin pathway through P53 to influence the proliferation and migration of hepatocellular carcinoma cells","volume":"5","author":"Tang","year":"2020","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"4739","DOI":"10.1038\/s41388-019-0754-1","article-title":"TRiC\/CCT chaperonins are essential for organ growth by interacting with insulin\/TOR signaling in Drosophila","volume":"38","author":"Kim","year":"2019","journal-title":"Oncogene"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"e201911058","DOI":"10.1083\/jcb.201911058","article-title":"Multiple actin networks coordinate mechanotransduction at the immunological synapse","volume":"219","author":"Blumenthal","year":"2020","journal-title":"J. Cell Biol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"951","DOI":"10.1083\/jcb.200801014","article-title":"MTOC translocation modulates IS formation and controls sustained T cell signaling","volume":"182","author":"Cabrero","year":"2008","journal-title":"J. Cell Biol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"eabb7242","DOI":"10.1126\/sciadv.abb7242","article-title":"The chaperonin CCT controls T cell receptor-driven 3D configuration of centrioles","volume":"6","author":"Chichon","year":"2020","journal-title":"Sci. Adv."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Lv, W., Shi, L., Pan, J., and Wang, S. (2022). Comprehensive prognostic and immunological analysis of CCT2 in pan-cancer. Front. Oncol., 12.","DOI":"10.3389\/fonc.2022.986990"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"eaau1935","DOI":"10.1126\/sciadv.aau1935","article-title":"The CCT chaperonin is a novel regulator of Ca2+ signaling through modulation of Orai1 trafficking","volume":"4","author":"Hodeify","year":"2018","journal-title":"Sci. Adv."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1016\/j.it.2015.02.008","article-title":"Overcoming T cell exhaustion in infection and cancer","volume":"36","author":"Pauken","year":"2015","journal-title":"Trends Immunol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1038\/nri.2017.108","article-title":"The diverse functions of the PD1 inhibitory pathway","volume":"18","author":"Sharpe","year":"2018","journal-title":"Nat. Rev. Immunol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1557","DOI":"10.1182\/blood-2008-05-078154","article-title":"CD4 T cells: Fates, functions, and faults","volume":"112","author":"Zhu","year":"2008","journal-title":"Blood"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"681","DOI":"10.1038\/s42003-021-02203-0","article-title":"The chaperonin CCT8 controls proteostasis essential for T cell maturation, selection, and function","volume":"4","author":"Oftedal","year":"2021","journal-title":"Commun. Biol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"2480","DOI":"10.1016\/j.apsb.2025.03.026","article-title":"Inhibition of CCT5-mediated asparagine biosynthesis and anti-PD-L1 produce synergistic antitumor effects in colorectal cancer","volume":"15","author":"Zhang","year":"2025","journal-title":"Acta Pharm. Sin. B"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"29294","DOI":"10.1074\/jbc.M203342200","article-title":"Bisindolylmaleimide VIII enhances DR5-mediated apoptosis through the MKK4\/JNK\/p38 kinase and the mitochondrial pathways","volume":"277","author":"Ohtsuka","year":"2002","journal-title":"J. Biol. Chem."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"984","DOI":"10.1038\/cr.2009.60","article-title":"An agonistic monoclonal antibody against DR5 induces ROS production, sustained JNK activation and Endo G release in Jurkat leukemia cells","volume":"19","author":"Chen","year":"2009","journal-title":"Cell Res."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"3123","DOI":"10.1016\/j.molcel.2023.07.031","article-title":"A hierarchical assembly pathway directs the unique subunit arrangement of TRiC\/CCT","volume":"83","author":"Collier","year":"2023","journal-title":"Mol. Cell"},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Chang, Y.X., Lin, Y.F., Chen, C.L., Huang, M.S., Hsiao, M., and Liang, P.H. (2020). Chaperonin-Containing TCP-1 Promotes Cancer Chemoresistance and Metastasis Through the AKT-GSK3beta-beta-Catenin and XIAP-Survivin Pathways. Cancers, 12.","DOI":"10.3390\/cancers12123865"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1038\/labinvest.2013.130","article-title":"Programmed death ligand-1 expression in non-small cell lung cancer","volume":"94","author":"Velcheti","year":"2014","journal-title":"Lab. Investig."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"429","DOI":"10.21037\/tlcr.2019.08.04","article-title":"The clinicopathological and prognostic significance of PD-L1 expression assessed by immunohistochemistry in lung cancer: A meta-analysis of 50 studies with 11,383 patients","volume":"8","author":"Li","year":"2019","journal-title":"Transl. Lung Cancer Res."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1158\/0008-5472.CAN-14-3362","article-title":"Control of PD-L1 Expression by Oncogenic Activation of the AKT-mTOR Pathway in Non-Small Cell Lung Cancer","volume":"76","author":"Lastwika","year":"2016","journal-title":"Cancer Res."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1360","DOI":"10.3892\/ijo.2016.3632","article-title":"The EGFR pathway is involved in the regulation of PD-L1 expression via the IL-6\/JAK\/STAT3 signaling pathway in EGFR-mutated non-small cell lung cancer","volume":"49","author":"Zhang","year":"2016","journal-title":"Int. J. Oncol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1189","DOI":"10.1016\/j.celrep.2017.04.031","article-title":"Interferon Receptor Signaling Pathways Regulating PD-L1 and PD-L2 Expression","volume":"19","author":"Shin","year":"2017","journal-title":"Cell Rep."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"619","DOI":"10.1016\/S1097-2765(03)00105-9","article-title":"An integrated stress response regulates amino acid metabolism and resistance to oxidative stress","volume":"11","author":"Harding","year":"2003","journal-title":"Mol. Cell"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"45495","DOI":"10.1074\/jbc.M406933200","article-title":"CHOP is involved in endoplasmic reticulum stress-induced apoptosis by enhancing DR5 expression in human carcinoma cells","volume":"279","author":"Yamaguchi","year":"2004","journal-title":"J. Biol. Chem."}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/15\/17\/1613\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T04:20:53Z","timestamp":1788927653000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/15\/17\/1613"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,4]]},"references-count":38,"journal-issue":{"issue":"17","published-online":{"date-parts":[[2026,9]]}},"alternative-id":["cells15171613"],"URL":"https:\/\/doi.org\/10.3390\/cells15171613","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,4]]}}}