{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,25]],"date-time":"2026-10-25T11:54:07Z","timestamp":1792929247583,"version":"4.5.0"},"reference-count":57,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2023,10,12]],"date-time":"2023-10-12T00:00:00Z","timestamp":1697068800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2023,10,12]],"date-time":"2023-10-12T00:00:00Z","timestamp":1697068800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81971463"],"award-info":[{"award-number":["81971463"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["J Transl Med"],"abstract":"<jats:title>Abstract<\/jats:title><jats:sec>\n                <jats:title>Background<\/jats:title>\n                <jats:p>The effectiveness of immune checkpoint inhibitors in treating gallbladder cancer (GBC) remains unsatisfactory. Recently, several new immune checkpoints have been identified. However, investigations exploring these immune checkpoints in GBC are limited. In this study, we aim to investigate the expression patterns and clinical implications of various immune checkpoints, and further characterize the spatial and quantitative heterogeneity of immune components in GBC.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Methods<\/jats:title>\n                <jats:p>We employed single and multiplex immunohistochemistry to evaluate the expression of five immune checkpoint markers and four immune cell markers in the primary tumor core, hepatic invasion margin, and liver metastasis. Subsequently, we analyzed their interrelationships and their prognostic significance.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>We observed a robust positive correlation between PD1\/TIM3 expression in GBC (R\u2009=\u20090.614, P\u2009&lt;\u20090.001). The co-expression of PD1\/TIM3 exhibited a synergistic effect in predicting poor prognosis among postoperative GBC patients. Further analysis revealed that the prognostic significance of PD1\/TIM3 was prominent in the subgroup with high infiltration of CD8\u2009+\u2009T cells (P\u2009&lt;\u20090.001). Multiplex immunohistochemistry reveals that PD1\u2009+\u2009TIM3\u2009+\u2009FOXP3\u2009+\u2009cells constitute a significant proportion of FOXP3\u2009+\u2009TILs in GBC tissue. Moreover, the co-high expression of PD1 and TIM3 is positively correlated with the accumulation of CD8\u2009+\u2009TILs at the hepatic invasion margin. Lastly, our findings indicated reduced expression levels of immune checkpoints and diminished immune cell infiltration in liver metastases compared to primary tumors.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusions<\/jats:title>\n                <jats:p>Increased co-expression of PD1\/TIM3 is associated with poor prognosis in GBC patients and is related to the heterogeneity of immune microenvironment between GBC primary tumor and its hepatic invasion margin or liver metastases, which may be a potential target for future immunotherapy of GBC.<\/jats:p>\n              <\/jats:sec>","DOI":"10.1186\/s12967-023-04589-3","type":"journal-article","created":{"date-parts":[[2023,10,12]],"date-time":"2023-10-12T17:02:06Z","timestamp":1697130126000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":26,"title":["Increased co-expression of PD1 and TIM3 is associated with poor prognosis and immune microenvironment heterogeneity in gallbladder cancer"],"prefix":"10.1186","volume":"21","author":[{"given":"Xing","family":"He","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yaorong","family":"Peng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gui","family":"He","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huilin","family":"Ye","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liqiang","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qixian","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juanyi","family":"Shi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sha","family":"Fu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jie","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhenyu","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenbin","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2023,10,12]]},"reference":[{"issue":"1","key":"4589_CR1","doi-asserted-by":"publisher","first-page":"69","DOI":"10.1038\/s41572-022-00398-y","volume":"8","author":"JC Roa","year":"2022","unstructured":"Roa JC, Garc\u00eda P, Kapoor VK, Maithel SK, Javle M, Koshiol J. Gallbladder cancer. Nature Rev Dis Primers. 2022;8(1):69.","journal-title":"Nature Rev Dis Primers"},{"issue":"10272","key":"4589_CR2","doi-asserted-by":"publisher","first-page":"428","DOI":"10.1016\/S0140-6736(21)00153-7","volume":"397","author":"JW Valle","year":"2021","unstructured":"Valle JW, Kelley RK, Nervi B, Oh DY, Zhu AX. Biliary tract cancer. Lancet. 2021;397(10272):428\u201344.","journal-title":"Lancet"},{"issue":"5","key":"4589_CR3","doi-asserted-by":"publisher","first-page":"328","DOI":"10.5582\/bst.2020.03240","volume":"14","author":"W Zhang","year":"2020","unstructured":"Zhang W, Zhou H, Wang Y, Zhang Z, Cao G, Song T, et al. Systemic treatment of advanced or recurrent biliary tract cancer. Biosci Trends. 2020;14(5):328\u201341.","journal-title":"Biosci Trends"},{"issue":"1","key":"4589_CR4","doi-asserted-by":"publisher","first-page":"23","DOI":"10.1186\/s12943-023-01720-2","volume":"22","author":"S Vivekanandhan","year":"2023","unstructured":"Vivekanandhan S, Bahr D, Kothari A, Ashary MA, Baksh M, Gabriel E. Immunotherapies in rare cancers. Mol Cancer. 2023;22(1):23.","journal-title":"Mol Cancer"},{"issue":"1","key":"4589_CR5","doi-asserted-by":"publisher","first-page":"37","DOI":"10.1038\/s41571-021-00552-7","volume":"19","author":"L Kraehenbuehl","year":"2022","unstructured":"Kraehenbuehl L, Weng CH, Eghbali S, Wolchok JD, Merghoub T. Enhancing immunotherapy in cancer by targeting emerging immunomodulatory pathways. Nat Rev Clin Oncol. 2022;19(1):37\u201350.","journal-title":"Nat Rev Clin Oncol"},{"key":"4589_CR6","doi-asserted-by":"publisher","DOI":"10.1158\/1538-7445.AM2019-CT183","author":"G Curigliano","year":"2019","unstructured":"Curigliano G, Gelderblom H, Mach N, Doi T, Tai WMD, Forde P, et al. Abstract CT183: Phase (Ph) I\/II study of MBG453\u00b1 spartalizumab (PDR001) in patients (pts) with advanced malignancies. Cancer Res. 2019. https:\/\/doi.org\/10.1158\/1538-7445.AM2019-CT183.","journal-title":"Cancer Res"},{"key":"4589_CR7","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2022.40.16_suppl.2504","author":"GS Falchook","year":"2022","unstructured":"Falchook GS, Ribas A, Davar D, Eroglu Z, Wang JS, Luke JJ, et al. Phase 1 trial of TIM-3 inhibitor cobolimab monotherapy and in combination with PD-1 inhibitors nivolumab or dostarlimab (AMBER). J Clin Oncol. 2022. https:\/\/doi.org\/10.1200\/JCO.2022.40.16_suppl.2504.","journal-title":"J Clin Oncol"},{"issue":"2","key":"4589_CR8","doi-asserted-by":"publisher","first-page":"169","DOI":"10.1016\/j.annonc.2021.11.002","volume":"33","author":"J Niu","year":"2022","unstructured":"Niu J, Maurice-Dror C, Lee DH, Kim DW, Nagrial A, Voskoboynik M, et al. First-in-human phase 1 study of the anti-TIGIT antibody vibostolimab as monotherapy or with pembrolizumab for advanced solid tumors, including non-small-cell lung cancer(\u2606). Ann Oncol Off J Eur Soc Med Oncol. 2022;33(2):169\u201380.","journal-title":"Ann Oncol Off J Eur Soc Med Oncol"},{"key":"4589_CR9","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2022.40.16_suppl.9003","author":"E Felip","year":"2022","unstructured":"Felip E, Majem M, Doger B, Clay TD, Carcereny E, Bondarenko I, et al. A phase II study (TACTI-002) in first-line metastatic non\u2013small cell lung carcinoma investigating eftilagimod alpha (soluble LAG-3 protein) and pembrolizumab: updated results from a PD-L1 unselected population. J Clin Oncol. 2022. https:\/\/doi.org\/10.1200\/JCO.2022.40.16_suppl.9003.","journal-title":"J Clin Oncol"},{"issue":"17","key":"4589_CR10","doi-asserted-by":"publisher","first-page":"4501","DOI":"10.1182\/blood-2010-10-310425","volume":"117","author":"Q Zhou","year":"2011","unstructured":"Zhou Q, Munger ME, Veenstra RG, Weigel BJ, Hirashima M, Munn DH, et al. Coexpression of Tim-3 and PD-1 identifies a CD8+ T-cell exhaustion phenotype in mice with disseminated acute myelogenous leukemia. Blood. 2011;117(17):4501\u201310.","journal-title":"Blood"},{"key":"4589_CR11","doi-asserted-by":"publisher","DOI":"10.1136\/jitc-2019-000294","author":"F Sun","year":"2020","unstructured":"Sun F, Guo ZS, Gregory AD, Shapiro SD, Xiao G, Qu Z. Dual but not single PD-1 or TIM-3 blockade enhances oncolytic virotherapy in refractory lung cancer. J Immunother Cancer. 2020. https:\/\/doi.org\/10.1136\/jitc-2019-000294.","journal-title":"J Immunother Cancer"},{"issue":"1","key":"4589_CR12","doi-asserted-by":"publisher","first-page":"75","DOI":"10.1186\/s40364-023-00513-5","volume":"11","author":"CS Yiong","year":"2023","unstructured":"Yiong CS, Lin TP, Lim VY, Toh TB, Yang VS. Biomarkers for immune checkpoint inhibition in sarcomas - are we close to clinical implementation? Biomarker research. 2023;11(1):75.","journal-title":"Biomarker research"},{"issue":"6","key":"4589_CR13","doi-asserted-by":"publisher","first-page":"345","DOI":"10.1038\/s41571-021-00473-5","volume":"18","author":"DB Doroshow","year":"2021","unstructured":"Doroshow DB, Bhalla S, Beasley MB, Sholl LM, Kerr KM, Gnjatic S, et al. PD-L1 as a biomarker of response to immune-checkpoint inhibitors. Nat Rev Clin Oncol. 2021;18(6):345\u201362.","journal-title":"Nat Rev Clin Oncol"},{"issue":"11","key":"4589_CR14","doi-asserted-by":"publisher","first-page":"2139","DOI":"10.1158\/0008-5472.CAN-15-0255","volume":"75","author":"MW Teng","year":"2015","unstructured":"Teng MW, Ngiow SF, Ribas A, Smyth MJ. Classifying cancers based on T-cell infiltration and PD-L1. Can Res. 2015;75(11):2139\u201345.","journal-title":"Can Res"},{"key":"4589_CR15","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2023.07.011","author":"SL Topalian","year":"2023","unstructured":"Topalian SL, Forde PM, Emens LA, Yarchoan M, Smith KN, Pardoll DM. Neoadjuvant immune checkpoint blockade: a window of opportunity to advance cancer immunotherapy. Cancer Cell. 2023. https:\/\/doi.org\/10.1016\/j.ccell.2023.07.011.","journal-title":"Cancer Cell"},{"issue":"3","key":"4589_CR16","doi-asserted-by":"publisher","first-page":"825","DOI":"10.1158\/1078-0432.CCR-15-3071","volume":"23","author":"H Cheng","year":"2017","unstructured":"Cheng H, Janakiram M, Borczuk A, Lin J, Qiu W, Liu H, et al. HHLA2, a new immune checkpoint member of the B7 family, is widely expressed in human lung cancer and associated with egfr mutational status. Clin Cancer Res Off J Am Assoc Cancer Res. 2017;23(3):825\u201332.","journal-title":"Clin Cancer Res Off J Am Assoc Cancer Res"},{"issue":"1","key":"4589_CR17","doi-asserted-by":"publisher","first-page":"16878","DOI":"10.1038\/s41598-017-17204-5","volume":"7","author":"P Bankhead","year":"2017","unstructured":"Bankhead P, Loughrey MB, Fern\u00e1ndez JA, Dombrowski Y, McArt DG, Dunne PD, et al. QuPath: open source software for digital pathology image analysis. Sci Rep. 2017;7(1):16878.","journal-title":"Sci Rep"},{"issue":"24","key":"4589_CR18","doi-asserted-by":"publisher","first-page":"6278","DOI":"10.1158\/1078-0432.CCR-15-2443","volume":"22","author":"ER Parra","year":"2016","unstructured":"Parra ER, Behrens C, Rodriguez-Canales J, Lin H, Mino B, Blando J, et al. Image analysis-based assessment of PD-L1 and tumor-associated immune cells density supports distinct intratumoral microenvironment groups in non-small cell lung carcinoma patients. Clin Cancer Res Off J Am Assoc Cancer Res. 2016;22(24):6278\u201389.","journal-title":"Clin Cancer Res Off J Am Assoc Cancer Res"},{"key":"4589_CR19","doi-asserted-by":"publisher","first-page":"71","DOI":"10.1038\/s41746-020-0275-x","volume":"3","author":"IP Nearchou","year":"2020","unstructured":"Nearchou IP, Gwyther BM, Georgiakakis ECT, Gavriel CG, Lillard K, Kajiwara Y, et al. Spatial immune profiling of the colorectal tumor microenvironment predicts good outcome in stage II patients. NPJ Digital Med. 2020;3:71.","journal-title":"NPJ Digital Med"},{"key":"4589_CR20","doi-asserted-by":"publisher","DOI":"10.1038\/s41422-023-00831-1","author":"L Wu","year":"2023","unstructured":"Wu L, Yan J, Bai Y, Chen F, Zou X, Xu J, et al. An invasive zone in human liver cancer identified by Stereo-seq promotes hepatocyte-tumor cell crosstalk, local immunosuppression and tumor progression. Cell Res. 2023. https:\/\/doi.org\/10.1038\/s41422-023-00831-1.","journal-title":"Cell Res"},{"issue":"21","key":"4589_CR21","doi-asserted-by":"publisher","first-page":"7252","DOI":"10.1158\/1078-0432.CCR-04-0713","volume":"10","author":"RL Camp","year":"2004","unstructured":"Camp RL, Dolled-Filhart M, Rimm DL. X-tile: a new bio-informatics tool for biomarker assessment and outcome-based cut-point optimization. Clin Cancer Res Off J Am Assoc Cancer Res. 2004;10(21):7252\u20139.","journal-title":"Clin Cancer Res Off J Am Assoc Cancer Res"},{"key":"4589_CR22","doi-asserted-by":"publisher","first-page":"1183619","DOI":"10.3389\/fphar.2023.1183619","volume":"14","author":"Y Zhou","year":"2023","unstructured":"Zhou Y, Yuan K, Yang Y, Ji Z, Zhou D, Ouyang J, et al. Gallbladder cancer: current and future treatment options. Front Pharmacol. 2023;14:1183619.","journal-title":"Front Pharmacol"},{"issue":"8","key":"4589_CR23","doi-asserted-by":"publisher","first-page":"760","DOI":"10.1016\/S2468-1253(23)00147-4","volume":"8","author":"M Pinter","year":"2023","unstructured":"Pinter M, Scheiner B, Pinato DJ. Immune checkpoint inhibitors in hepatocellular carcinoma: emerging challenges in clinical practice. Lancet Gastroenterol Hepatol. 2023;8(8):760\u201370.","journal-title":"Lancet Gastroenterol Hepatol"},{"issue":"7","key":"4589_CR24","doi-asserted-by":"publisher","first-page":"529","DOI":"10.1038\/s41573-022-00493-5","volume":"21","author":"TK Kim","year":"2022","unstructured":"Kim TK, Vandsemb EN, Herbst RS, Chen L. Adaptive immune resistance at the tumour site: mechanisms and therapeutic opportunities. Nat Rev Drug Discovery. 2022;21(7):529\u201340.","journal-title":"Nat Rev Drug Discovery"},{"issue":"3","key":"4589_CR25","doi-asserted-by":"publisher","first-page":"197","DOI":"10.1038\/s41573-018-0007-y","volume":"18","author":"J Galon","year":"2019","unstructured":"Galon J, Bruni D. Approaches to treat immune hot, altered and cold tumours with combination immunotherapies. Nat Rev Drug Discovery. 2019;18(3):197\u2013218.","journal-title":"Nat Rev Drug Discovery"},{"issue":"1","key":"4589_CR26","doi-asserted-by":"publisher","first-page":"243","DOI":"10.1186\/s12885-018-4147-6","volume":"18","author":"P Flux\u00e1","year":"2018","unstructured":"Flux\u00e1 P, Rojas-Sep\u00falveda D, Gleisner MA, Tittarelli A, Villegas P, Tapia L, et al. High CD8(+) and absence of Foxp3(+) T lymphocytes infiltration in gallbladder tumors correlate with prolonged patients survival. BMC Cancer. 2018;18(1):243.","journal-title":"BMC Cancer"},{"issue":"4","key":"4589_CR27","doi-asserted-by":"publisher","first-page":"622","DOI":"10.1111\/his.13669","volume":"73","author":"A Neyaz","year":"2018","unstructured":"Neyaz A, Husain N, Kumari S, Gupta S, Shukla S, Arshad S, et al. Clinical relevance of PD-L1 expression in gallbladder cancer: a potential target for therapy. Histopathology. 2018;73(4):622\u201333.","journal-title":"Histopathology"},{"issue":"3","key":"4589_CR28","doi-asserted-by":"publisher","first-page":"817","DOI":"10.1111\/cas.14302","volume":"111","author":"X Bo","year":"2020","unstructured":"Bo X, Wang J, Wang C, Nan L, Gao Z, Xin Y, et al. High infiltration of mast cells is associated with improved response to adjuvant chemotherapy in gallbladder cancer. Cancer Sci. 2020;111(3):817\u201325.","journal-title":"Cancer Sci"},{"issue":"19","key":"4589_CR29","doi-asserted-by":"publisher","first-page":"5351","DOI":"10.1158\/1078-0432.CCR-13-0035","volume":"19","author":"OK Afanasiev","year":"2013","unstructured":"Afanasiev OK, Yelistratova L, Miller N, Nagase K, Paulson K, Iyer JG, et al. Merkel polyomavirus-specific T cells fluctuate with merkel cell carcinoma burden and express therapeutically targetable PD-1 and Tim-3 exhaustion markers. Clinical cancer Res Off J Am Assoc Cancer Res. 2013;19(19):5351\u201360.","journal-title":"Clinical cancer Res Off J Am Assoc Cancer Res"},{"issue":"10","key":"4589_CR30","doi-asserted-by":"publisher","first-page":"2187","DOI":"10.1084\/jem.20100643","volume":"207","author":"K Sakuishi","year":"2010","unstructured":"Sakuishi K, Apetoh L, Sullivan JM, Blazar BR, Kuchroo VK, Anderson AC. Targeting Tim-3 and PD-1 pathways to reverse T cell exhaustion and restore anti-tumor immunity. J Exp Med. 2010;207(10):2187\u201394.","journal-title":"J Exp Med"},{"issue":"10","key":"4589_CR31","doi-asserted-by":"publisher","first-page":"2175","DOI":"10.1084\/jem.20100637","volume":"207","author":"J Fourcade","year":"2010","unstructured":"Fourcade J, Sun Z, Benallaoua M, Guillaume P, Luescher IF, Sander C, et al. Upregulation of Tim-3 and PD-1 expression is associated with tumor antigen-specific CD8+ T cell dysfunction in melanoma patients. J Exp Med. 2010;207(10):2175\u201386.","journal-title":"J Exp Med"},{"issue":"Pt 3","key":"4589_CR32","doi-asserted-by":"publisher","first-page":"137","DOI":"10.1016\/j.semcancer.2022.03.014","volume":"86","author":"S Gaikwad","year":"2022","unstructured":"Gaikwad S, Agrawal MY, Kaushik I, Ramachandran S, Srivastava SK. Immune checkpoint proteins: signaling mechanisms and molecular interactions in cancer immunotherapy. Semin Cancer Biol. 2022;86(Pt 3):137\u201350.","journal-title":"Semin Cancer Biol"},{"issue":"1","key":"4589_CR33","doi-asserted-by":"publisher","first-page":"832","DOI":"10.1038\/s41467-021-21099-2","volume":"12","author":"R Yang","year":"2021","unstructured":"Yang R, Sun L, Li CF, Wang YH, Yao J, Li H, et al. Galectin-9 interacts with PD-1 and TIM-3 to regulate T cell death and is a target for cancer immunotherapy. Nat Commun. 2021;12(1):832.","journal-title":"Nat Commun"},{"issue":"1","key":"4589_CR34","doi-asserted-by":"publisher","first-page":"766","DOI":"10.1186\/s12885-018-4651-8","volume":"18","author":"J Lin","year":"2018","unstructured":"Lin J, Long J, Wan X, Chen J, Bai Y, Wang A, et al. Classification of gallbladder cancer by assessment of CD8(+) TIL and PD-L1 expression. BMC Cancer. 2018;18(1):766.","journal-title":"BMC Cancer"},{"key":"4589_CR35","doi-asserted-by":"publisher","DOI":"10.1016\/j.trecan.2023.07.015","author":"JH Kang","year":"2023","unstructured":"Kang JH, Zappasodi R. Modulating Treg stability to improve cancer immunotherapy. Trends Cancer. 2023. https:\/\/doi.org\/10.1016\/j.trecan.2023.07.015.","journal-title":"Trends Cancer"},{"key":"4589_CR36","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.85935","author":"DE Lowther","year":"2016","unstructured":"Lowther DE, Goods BA, Lucca LE, Lerner BA, Raddassi K, van Dijk D, et al. PD-1 marks dysfunctional regulatory T cells in malignant gliomas. JCI Insight. 2016. https:\/\/doi.org\/10.1172\/jci.insight.85935.","journal-title":"JCI Insight"},{"issue":"18","key":"4589_CR37","doi-asserted-by":"publisher","first-page":"4529","DOI":"10.1158\/1078-0432.CCR-17-1350","volume":"24","author":"Z Liu","year":"2018","unstructured":"Liu Z, McMichael EL, Shayan G, Li J, Chen K, Srivastava R, et al. Novel effector phenotype of Tim-3(+) regulatory T cells leads to enhanced suppressive function in head and neck cancer patients. Clin Cancer Res Off J Am Assoc Cancer Res. 2018;24(18):4529\u201338.","journal-title":"Clin Cancer Res Off J Am Assoc Cancer Res"},{"issue":"2","key":"4589_CR38","doi-asserted-by":"publisher","first-page":"316","DOI":"10.1016\/j.immuni.2016.01.013","volume":"44","author":"ME Turnis","year":"2016","unstructured":"Turnis ME, Sawant DV, Szymczak-Workman AL, Andrews LP, Delgoffe GM, Yano H, et al. Interleukin-35 limits anti-tumor immunity. Immunity. 2016;44(2):316\u201329.","journal-title":"Immunity"},{"key":"4589_CR39","doi-asserted-by":"publisher","first-page":"6072","DOI":"10.1038\/ncomms7072","volume":"6","author":"C Zhu","year":"2015","unstructured":"Zhu C, Sakuishi K, Xiao S, Sun Z, Zaghouani S, Gu G, et al. An IL-27\/NFIL3 signalling axis drives Tim-3 and IL-10 expression and T-cell dysfunction. Nat Commun. 2015;6:6072.","journal-title":"Nat Commun"},{"issue":"7710","key":"4589_CR40","doi-asserted-by":"publisher","first-page":"454","DOI":"10.1038\/s41586-018-0206-z","volume":"558","author":"N Chihara","year":"2018","unstructured":"Chihara N, Madi A, Kondo T, Zhang H, Acharya N, Singer M, et al. Induction and transcriptional regulation of the co-inhibitory gene module in T cells. Nature. 2018;558(7710):454\u20139.","journal-title":"Nature"},{"issue":"7","key":"4589_CR41","doi-asserted-by":"publisher","first-page":"2395","DOI":"10.1172\/JCI45138","volume":"122","author":"S Gupta","year":"2012","unstructured":"Gupta S, Thornley TB, Gao W, Larocca R, Turka LA, Kuchroo VK, et al. Allograft rejection is restrained by short-lived TIM-3+PD-1+Foxp3+ Tregs. J Clin Investig. 2012;122(7):2395\u2013404.","journal-title":"J Clin Investig"},{"issue":"1","key":"4589_CR42","doi-asserted-by":"publisher","first-page":"116","DOI":"10.1186\/s12943-020-01234-1","volume":"19","author":"C Li","year":"2020","unstructured":"Li C, Jiang P, Wei S, Xu X, Wang J. Regulatory T cells in tumor microenvironment: new mechanisms, potential therapeutic strategies and future prospects. Mol Cancer. 2020;19(1):116.","journal-title":"Mol Cancer"},{"issue":"6","key":"4589_CR43","doi-asserted-by":"publisher","first-page":"724","DOI":"10.1038\/s41590-019-0346-9","volume":"20","author":"DV Sawant","year":"2019","unstructured":"Sawant DV, Yano H, Chikina M, Zhang Q, Liao M, Liu C, et al. Adaptive plasticity of IL-10(+) and IL-35(+) T(reg) cells cooperatively promotes tumor T cell exhaustion. Nat Immunol. 2019;20(6):724\u201335.","journal-title":"Nat Immunol"},{"issue":"7","key":"4589_CR44","doi-asserted-by":"publisher","first-page":"1613","DOI":"10.1016\/j.immuni.2023.06.003","volume":"56","author":"MA Moreno Ayala","year":"2023","unstructured":"Moreno Ayala MA, Campbell TF, Zhang C, Dahan N, Bockman A, Prakash V, et al. CXCR3 expression in regulatory T cells drives interactions with type I dendritic cells in tumors to restrict CD8(+) T cell antitumor immunity. Immunity. 2023;56(7):1613-30.e5.","journal-title":"Immunity"},{"issue":"12","key":"4589_CR45","doi-asserted-by":"publisher","first-page":"5801","DOI":"10.4049\/jimmunol.1401936","volume":"194","author":"HJ Park","year":"2015","unstructured":"Park HJ, Park JS, Jeong YH, Son J, Ban YH, Lee BH, et al. PD-1 upregulated on regulatory T cells during chronic virus infection enhances the suppression of CD8+ T cell immune response via the interaction with PD-L1 expressed on CD8+ T cells. J Immunol. 2015;194(12):5801\u201311.","journal-title":"J Immunol"},{"issue":"1","key":"4589_CR46","doi-asserted-by":"publisher","first-page":"339","DOI":"10.1186\/s40425-019-0785-8","volume":"7","author":"HR Kim","year":"2019","unstructured":"Kim HR, Park HJ, Son J, Lee JG, Chung KY, Cho NH, et al. Tumor microenvironment dictates regulatory T cell phenotype: upregulated immune checkpoints reinforce suppressive function. J Immunother Cancer. 2019;7(1):339.","journal-title":"J Immunother Cancer"},{"issue":"9","key":"4589_CR47","doi-asserted-by":"publisher","first-page":"877","DOI":"10.1016\/S1470-2045(09)70186-X","volume":"10","author":"L Laghi","year":"2009","unstructured":"Laghi L, Bianchi P, Miranda E, Balladore E, Pacetti V, Grizzi F, et al. CD3+ cells at the invasive margin of deeply invading (pT3-T4) colorectal cancer and risk of post-surgical metastasis: a longitudinal study. Lancet Oncol. 2009;10(9):877\u201384.","journal-title":"Lancet Oncol"},{"issue":"5","key":"4589_CR48","doi-asserted-by":"publisher","first-page":"1341","DOI":"10.1016\/j.cell.2020.07.005","volume":"182","author":"CM Sch\u00fcrch","year":"2020","unstructured":"Sch\u00fcrch CM, Bhate SS, Barlow GL, Phillips DJ, Noti L, Zlobec I, et al. Coordinated cellular neighborhoods orchestrate antitumoral immunity at the colorectal cancer invasive front. Cell. 2020;182(5):1341-59.e19.","journal-title":"Cell"},{"issue":"4","key":"4589_CR49","doi-asserted-by":"publisher","first-page":"609","DOI":"10.1158\/2326-6066.CIR-18-0377","volume":"7","author":"IP Nearchou","year":"2019","unstructured":"Nearchou IP, Lillard K, Gavriel CG, Ueno H, Harrison DJ, Caie PD. Automated analysis of lymphocytic infiltration, tumor budding, and their spatial relationship improves prognostic accuracy in colorectal cancer. Cancer Immunol Res. 2019;7(4):609\u201320.","journal-title":"Cancer Immunol Res"},{"issue":"17","key":"4589_CR50","doi-asserted-by":"publisher","first-page":"5670","DOI":"10.1158\/0008-5472.CAN-11-0268","volume":"71","author":"N Halama","year":"2011","unstructured":"Halama N, Michel S, Kloor M, Zoernig I, Benner A, Spille A, et al. Localization and density of immune cells in the invasive margin of human colorectal cancer liver metastases are prognostic for response to chemotherapy. Can Res. 2011;71(17):5670\u20137.","journal-title":"Can Res"},{"issue":"11","key":"4589_CR51","doi-asserted-by":"publisher","first-page":"1423","DOI":"10.1038\/nm.3394","volume":"19","author":"DF Quail","year":"2013","unstructured":"Quail DF, Joyce JA. Microenvironmental regulation of tumor progression and metastasis. Nat Med. 2013;19(11):1423\u201337.","journal-title":"Nat Med"},{"issue":"8","key":"4589_CR52","doi-asserted-by":"publisher","first-page":"585","DOI":"10.1038\/s41422-023-00831-1","volume":"33","author":"L Wu","year":"2023","unstructured":"Wu L, Yan J, Bai Y, Chen F, Zou X, Xu J, et al. An invasive zone in human liver cancer identified by stereo-seq promotes hepatocyte-tumor cell crosstalk, local immunosuppression and tumor progression. Cell Res. 2023;33(8):585\u2013603.","journal-title":"Cell Res"},{"issue":"1","key":"4589_CR53","doi-asserted-by":"publisher","first-page":"217","DOI":"10.1016\/j.jhep.2022.09.004","volume":"78","author":"JJ Harding","year":"2023","unstructured":"Harding JJ, Khalil DN, Fabris L, Abou-Alfa GK. Rational development of combination therapies for biliary tract cancers. J Hepatol. 2023;78(1):217\u201328.","journal-title":"J Hepatol"},{"issue":"12","key":"4589_CR54","doi-asserted-by":"publisher","first-page":"1730","DOI":"10.1111\/cas.13101","volume":"107","author":"R Ogiya","year":"2016","unstructured":"Ogiya R, Niikura N, Kumaki N, Bianchini G, Kitano S, Iwamoto T, et al. Comparison of tumor-infiltrating lymphocytes between primary and metastatic tumors in breast cancer patients. Cancer Sci. 2016;107(12):1730\u20135.","journal-title":"Cancer Sci"},{"issue":"1","key":"4589_CR55","doi-asserted-by":"publisher","first-page":"371","DOI":"10.1186\/s12885-018-4276-y","volume":"18","author":"M Shibutani","year":"2018","unstructured":"Shibutani M, Maeda K, Nagahara H, Fukuoka T, Matsutani S, Kashiwagi S, et al. A comparison of the local immune status between the primary and metastatic tumor in colorectal cancer: a retrospective study. BMC Cancer. 2018;18(1):371.","journal-title":"BMC Cancer"},{"issue":"1","key":"4589_CR56","doi-asserted-by":"publisher","first-page":"10","DOI":"10.1186\/s12885-018-5211-y","volume":"19","author":"MS You","year":"2019","unstructured":"You MS, Ryu JK, Choi YH, Choi JH, Huh G, Paik WH, et al. Therapeutic outcomes and prognostic factors in unresectable gallbladder cancer treated with gemcitabine plus cisplatin. BMC Cancer. 2019;19(1):10.","journal-title":"BMC Cancer"},{"issue":"1","key":"4589_CR57","doi-asserted-by":"publisher","first-page":"152","DOI":"10.1186\/s12876-022-02234-9","volume":"22","author":"R Higuchi","year":"2022","unstructured":"Higuchi R, Ono H, Matsuyama R, Takemura Y, Kobayashi S, Otsubo T, et al. Examination of the characteristics of long-term survivors among patients with gallbladder cancer with liver metastasis who underwent surgical treatment: a retrospective multicenter study (ACRoS1406). BMC Gastroenterol. 2022;22(1):152.","journal-title":"BMC Gastroenterol"}],"updated-by":[{"DOI":"10.1186\/s12967-024-04905-5","type":"correction","label":"Correction","source":"publisher","updated":{"date-parts":[[2024,1,30]],"date-time":"2024-01-30T00:00:00Z","timestamp":1706572800000}}],"container-title":["Journal of Translational Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s12967-023-04589-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s12967-023-04589-3\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s12967-023-04589-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,1,30]],"date-time":"2024-01-30T12:12:15Z","timestamp":1706616735000},"score":1,"resource":{"primary":{"URL":"https:\/\/translational-medicine.biomedcentral.com\/articles\/10.1186\/s12967-023-04589-3"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,10,12]]},"references-count":57,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2023,12]]}},"alternative-id":["4589"],"URL":"https:\/\/doi.org\/10.1186\/s12967-023-04589-3","relation":{"correction":[{"id-type":"doi","id":"10.1186\/s12967-024-04905-5","asserted-by":"object"}]},"ISSN":["1479-5876"],"issn-type":[{"value":"1479-5876","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,10,12]]},"assertion":[{"value":"2 August 2023","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"3 October 2023","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"12 October 2023","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"30 January 2024","order":4,"name":"change_date","label":"Change Date","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"Correction","order":5,"name":"change_type","label":"Change Type","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"A Correction to this paper has been published:","order":6,"name":"change_details","label":"Change Details","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"https:\/\/doi.org\/10.1186\/s12967-024-04905-5","URL":"https:\/\/doi.org\/10.1186\/s12967-024-04905-5","order":7,"name":"change_details","label":"Change Details","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The study was in accordance with protocols approved by Medical Ethics Committee, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, China (ID: SYSKY-2023-294-01). All samples and data were obtained with informed consent.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"All authors confirm their consent for publication the manuscript.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The authors declare no potential competing interests.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"717"}}