{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T05:59:24Z","timestamp":1790834364170,"version":"4.1.0"},"reference-count":43,"publisher":"National Academy of Sciences","issue":"29","license":[{"start":{"date-parts":[[2017,7,3]],"date-time":"2017-07-03T00:00:00Z","timestamp":1499040000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/www.pnas.org\/site\/misc\/userlicense.xhtml"}],"funder":[{"DOI":"10.13039\/501100001349","name":"MOH | National Medical Research Council","doi-asserted-by":"publisher","award":["MOHIAFCAT2001"],"award-info":[{"award-number":["MOHIAFCAT2001"]}],"id":[{"id":"10.13039\/501100001349","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001349","name":"MOH | National Medical Research Council","doi-asserted-by":"publisher","award":["TCR15Jun006"],"award-info":[{"award-number":["TCR15Jun006"]}],"id":[{"id":"10.13039\/501100001349","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001349","name":"MOH | National Medical Research Council","doi-asserted-by":"publisher","award":["CIRG16may048"],"award-info":[{"award-number":["CIRG16may048"]}],"id":[{"id":"10.13039\/501100001349","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001446","name":"Economic Development Board - Singapore","doi-asserted-by":"publisher","award":["BMRC-EDB IAF: IAF311020"],"award-info":[{"award-number":["BMRC-EDB IAF: IAF311020"]}],"id":[{"id":"10.13039\/501100001446","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001349","name":"MOH | National Medical Research Council","doi-asserted-by":"publisher","award":["NMRC\/STaR\/020\/2013"],"award-info":[{"award-number":["NMRC\/STaR\/020\/2013"]}],"id":[{"id":"10.13039\/501100001349","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2017,7,18]]},"abstract":"<jats:title>Significance<\/jats:title>\n                  <jats:p>The roles of tumor-infiltrating leukocytes in mediating cancer progression are well recognized, but a multidimensional analysis of the entire cancer immune system is lacking. Here, we dissected the cancer-immune landscape in hepatocellular carcinoma (HCC) across tumor, nontumor, and peripheral blood cells using time-of-flight mass cytometry, multiplex immunofluorescence tissue staining, and NanoString analysis. We identified various immune subsets that were enriched in the tumor microenvironment and their potential impact on the tumor immunity based on their detailed phenotypes. This study has validated the concept of a cancer-immune gradient and demonstrated in primary HCC that immune-cell subsets become progressively suppressive as they traverse the nontumor to tumor microenvironment. These data have opened avenues for the design of immunotherapeutics in HCC.<\/jats:p>","DOI":"10.1073\/pnas.1706559114","type":"journal-article","created":{"date-parts":[[2017,7,3]],"date-time":"2017-07-03T20:50:19Z","timestamp":1499115019000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":212,"title":["Delineation of an immunosuppressive gradient in hepatocellular carcinoma using high-dimensional proteomic and transcriptomic analyses"],"prefix":"10.1073","volume":"114","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5617-0936","authenticated-orcid":false,"given":"Valerie","family":"Chew","sequence":"first","affiliation":[{"name":"SingHealth Translational Immunology and Inflammation Centre, Duke University\u2013National University of Singapore Medical School, Singapore 169856;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liyun","family":"Lai","sequence":"additional","affiliation":[{"name":"SingHealth Translational Immunology and Inflammation Centre, Duke University\u2013National University of Singapore Medical School, Singapore 169856;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lu","family":"Pan","sequence":"additional","affiliation":[{"name":"SingHealth Translational Immunology and Inflammation Centre, Duke University\u2013National University of Singapore Medical School, Singapore 169856;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chun Jye","family":"Lim","sequence":"additional","affiliation":[{"name":"SingHealth Translational Immunology and Inflammation Centre, Duke University\u2013National University of Singapore Medical School, Singapore 169856;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juntao","family":"Li","sequence":"additional","affiliation":[{"name":"SingHealth Translational Immunology and Inflammation Centre, Duke University\u2013National University of Singapore Medical School, Singapore 169856;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raymond","family":"Ong","sequence":"additional","affiliation":[{"name":"SingHealth Translational Immunology and Inflammation Centre, Duke University\u2013National University of Singapore Medical School, Singapore 169856;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Camillus","family":"Chua","sequence":"additional","affiliation":[{"name":"SingHealth Translational Immunology and Inflammation Centre, Duke University\u2013National University of Singapore Medical School, Singapore 169856;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing Yao","family":"Leong","sequence":"additional","affiliation":[{"name":"SingHealth Translational Immunology and Inflammation Centre, Duke University\u2013National University of Singapore Medical School, Singapore 169856;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kiat Hon","family":"Lim","sequence":"additional","affiliation":[{"name":"Department of Anatomical Pathology, Singapore General Hospital, Singapore 169856;"},{"name":"Duke University\u2013National University of Singapore Medical School, Singapore 169857;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Han Chong","family":"Toh","sequence":"additional","affiliation":[{"name":"Duke University\u2013National University of Singapore Medical School, Singapore 169857;"},{"name":"National Cancer Centre, Singapore 169610;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ser Yee","family":"Lee","sequence":"additional","affiliation":[{"name":"Duke University\u2013National University of Singapore Medical School, Singapore 169857;"},{"name":"National Cancer Centre, Singapore 169610;"},{"name":"Department of Hepatopancreatobiliary and Transplant Surgery, Singapore General Hospital, Singapore 169856"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chung Yip","family":"Chan","sequence":"additional","affiliation":[{"name":"Duke University\u2013National University of Singapore Medical School, Singapore 169857;"},{"name":"National Cancer Centre, Singapore 169610;"},{"name":"Department of Hepatopancreatobiliary and Transplant Surgery, Singapore General Hospital, Singapore 169856"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brian K. P.","family":"Goh","sequence":"additional","affiliation":[{"name":"Duke University\u2013National University of Singapore Medical School, Singapore 169857;"},{"name":"National Cancer Centre, Singapore 169610;"},{"name":"Department of Hepatopancreatobiliary and Transplant Surgery, Singapore General Hospital, Singapore 169856"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander","family":"Chung","sequence":"additional","affiliation":[{"name":"Duke University\u2013National University of Singapore Medical School, Singapore 169857;"},{"name":"National Cancer Centre, Singapore 169610;"},{"name":"Department of Hepatopancreatobiliary and Transplant Surgery, Singapore General Hospital, Singapore 169856"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pierce K. H.","family":"Chow","sequence":"additional","affiliation":[{"name":"Duke University\u2013National University of Singapore Medical School, Singapore 169857;"},{"name":"National Cancer Centre, Singapore 169610;"},{"name":"Department of Hepatopancreatobiliary and Transplant Surgery, Singapore General Hospital, Singapore 169856"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Salvatore","family":"Albani","sequence":"additional","affiliation":[{"name":"SingHealth Translational Immunology and Inflammation Centre, Duke University\u2013National University of Singapore Medical School, Singapore 169856;"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2017,7,3]]},"reference":[{"key":"e_1_3_3_1_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrc3245"},{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2015.02.038"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.342.6165.1432"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrclinonc.2014.221"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1136\/gutjnl-2014-307990"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1003466"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.4254\/wjh.v7.i7.980"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1189\/jlb.1212631"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1002\/ijc.29210"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMra1001683"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1159\/000367758"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1136\/gutjnl-2011-300509"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2009.07.013"},{"key":"e_1_3_3_14_2","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2013.01.002"},{"key":"e_1_3_3_15_2","doi-asserted-by":"publisher","DOI":"10.4161\/21624011.2014.954919"},{"key":"e_1_3_3_16_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00262-004-0593-x"},{"key":"e_1_3_3_17_2","doi-asserted-by":"publisher","DOI":"10.1038\/nbt.2938"},{"key":"e_1_3_3_18_2","doi-asserted-by":"publisher","DOI":"10.1002\/cyto.a.22640"},{"key":"e_1_3_3_19_2","doi-asserted-by":"publisher","DOI":"10.1002\/cyto.a.22271"},{"key":"e_1_3_3_20_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1321405111"},{"key":"e_1_3_3_21_2","doi-asserted-by":"publisher","DOI":"10.1136\/gutjnl-2015-310814"},{"key":"e_1_3_3_22_2","doi-asserted-by":"publisher","DOI":"10.1002\/jcp.24886"},{"key":"e_1_3_3_23_2","doi-asserted-by":"publisher","DOI":"10.1007\/s12032-011-0006-x"},{"key":"e_1_3_3_24_2","doi-asserted-by":"crossref","first-page":"748","DOI":"10.1002\/ijc.25464","article-title":"Prognostic significance of regulatory T cells in tumor","volume":"127","author":"Wilke CM","year":"2010","unstructured":"CM Wilke, K Wu, E Zhao, G Wang, W Zou, Prognostic significance of regulatory T cells in tumor. Int J Cancer 127, 748\u2013758 (2010).","journal-title":"Int J Cancer"},{"key":"e_1_3_3_25_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrclinonc.2013.208-c1"},{"key":"e_1_3_3_26_2","doi-asserted-by":"crossref","unstructured":"DE Lowther PD-1 marks dysfunctional regulatory T cells in malignant gliomas. JCI Insight 1(5). (2016).","DOI":"10.1172\/jci.insight.85935"},{"key":"e_1_3_3_27_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1401936"},{"key":"e_1_3_3_28_2","doi-asserted-by":"publisher","DOI":"10.1038\/ni.2046"},{"key":"e_1_3_3_29_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2016.01.018"},{"key":"e_1_3_3_30_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.181.12.8391"},{"key":"e_1_3_3_31_2","doi-asserted-by":"publisher","DOI":"10.1002\/eji.200636251"},{"key":"e_1_3_3_32_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20091021"},{"key":"e_1_3_3_33_2","doi-asserted-by":"publisher","DOI":"10.1038\/ni1467"},{"key":"e_1_3_3_34_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1359-6101(03)00049-2"},{"key":"e_1_3_3_35_2","doi-asserted-by":"publisher","DOI":"10.1186\/s12943-015-0394-1"},{"key":"e_1_3_3_36_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jtbi.2013.03.017"},{"key":"e_1_3_3_37_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.178.9.5595"},{"key":"e_1_3_3_38_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1402711"},{"key":"e_1_3_3_39_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.onc.1209559"},{"key":"e_1_3_3_40_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.188.2.341"},{"key":"e_1_3_3_41_2","doi-asserted-by":"publisher","DOI":"10.1038\/cddis.2015.42"},{"key":"e_1_3_3_42_2","doi-asserted-by":"publisher","DOI":"10.1186\/s12985-016-0473-y"},{"key":"e_1_3_3_43_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0050946"}],"container-title":["Proceedings of the National Academy of Sciences"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/www.pnas.org\/syndication\/doi\/10.1073\/pnas.1706559114","content-type":"unspecified","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/pnas.org\/doi\/pdf\/10.1073\/pnas.1706559114","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,6,25]],"date-time":"2024-06-25T02:08:08Z","timestamp":1719281288000},"score":1,"resource":{"primary":{"URL":"https:\/\/pnas.org\/doi\/full\/10.1073\/pnas.1706559114"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,7,3]]},"references-count":43,"journal-issue":{"issue":"29","published-print":{"date-parts":[[2017,7,18]]}},"alternative-id":["10.1073\/pnas.1706559114"],"URL":"https:\/\/doi.org\/10.1073\/pnas.1706559114","relation":{},"ISSN":["0027-8424","1091-6490"],"issn-type":[{"value":"0027-8424","type":"print"},{"value":"1091-6490","type":"electronic"}],"subject":[],"published":{"date-parts":[[2017,7,3]]},"assertion":[{"value":"2017-07-03","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}