{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,6]],"date-time":"2026-11-06T07:01:30Z","timestamp":1793948490634,"version":"4.8.0"},"reference-count":37,"publisher":"BMJ","issue":"3","license":[{"start":{"date-parts":[[2026,3,30]],"date-time":"2026-03-30T00:00:00Z","timestamp":1774828800000},"content-version":"unspecified","delay-in-days":29,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/100009619","name":"Japan Agency for Medical Research and Development","doi-asserted-by":"crossref","award":["JP23ck0106793"],"award-info":[{"award-number":["JP23ck0106793"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100009619","name":"Japan Agency for Medical Research and Development","doi-asserted-by":"crossref","award":["JP24ama221410"],"award-info":[{"award-number":["JP24ama221410"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100009619","name":"Japan Agency for Medical Research and Development","doi-asserted-by":"crossref","award":["JP24fk0210131"],"award-info":[{"award-number":["JP24fk0210131"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100009619","name":"Japan Agency for Medical Research and Development","doi-asserted-by":"crossref","award":["JP25fk0310537"],"award-info":[{"award-number":["JP25fk0310537"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100001700","name":"Ministry of Education, Culture, Sports, Science, and Technology, Japan","doi-asserted-by":"crossref","award":["23H02893"],"award-info":[{"award-number":["23H02893"]}],"id":[{"id":"10.13039\/501100001700","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100001700","name":"Ministry of Education, Culture, Sports, Science, and Technology, Japan","doi-asserted-by":"crossref","award":["24K18972"],"award-info":[{"award-number":["24K18972"]}],"id":[{"id":"10.13039\/501100001700","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["J Immunother Cancer"],"accepted":{"date-parts":[[2026,3,16]]},"published-print":{"date-parts":[[2026,3]]},"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Combination immunotherapies such as atezolizumab plus bevacizumab (Atez\/Bev) and durvalumab plus tremelimumab (Dur\/Tre) improve outcomes in advanced hepatocellular carcinoma (HCC), yet systemic immune mechanisms underlying response remain incompletely defined.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We performed single-cell RNA sequencing with CITE-seq on peripheral blood mononuclear cells from 19 advanced HCC patients (Atez\/Bev: 5 responders (R), 5 non-responders (NR); Dur\/Tre: 4 R, 5 NR) before and during treatment, yielding 345\u2009962 single-cell transcriptomes spanning 22 immune cell clusters. Analysis included transcriptional profiling, gene set enrichment analysis, T cell receptor (TCR) repertoire analysis, and CellChat-based intercellular communication modeling.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Baseline comparisons revealed distinct systemic immune states by etiology: non-viral HCC exhibited CD8\n                      <jats:sup>+<\/jats:sup>\n                      T cells with heightened cytotoxic and memory-associated signatures. Under Atez\/Bev, CD14\n                      <jats:sup>+<\/jats:sup>\n                      monocytes in responders were reprogrammed toward antigen-presenting and lymphocyte-supporting functions, while PRKCH\n                      <jats:sup>+<\/jats:sup>\n                      NK cells acquired a robust cytotoxic program reinforced by monocyte\u2013NK interactions via ICAM\u2013integrin and HLA-E\u2013NKG2C axes. In contrast, Dur\/Tre responders exhibited CD14\n                      <jats:sup>+<\/jats:sup>\n                      monocyte programs enriched in inflammatory and interferon-driven antigen presentation, alongside transcriptional reprogramming of CD8\n                      <jats:sup>+<\/jats:sup>\n                      central memory T cells into an effector-ready state with strong crosstalk to monocytes. TCR analysis revealed regimen-specific differences: clonotype expansion occurred irrespective of response under Atez\/Bev, whereas Dur\/Tre responders showed both clonotype expansion and higher pretreatment CD8\n                      <jats:sup>+<\/jats:sup>\n                      T cell diversity, with expanded clones displaying cytotoxic and interferon-responsive profiles. Pretreatment immune composition, including na\u00efve CD4\n                      <jats:sup>+<\/jats:sup>\n                      T cells and PRKCH\n                      <jats:sup>+<\/jats:sup>\n                      NK cells for Atez\/Bev and conventional dendritic cells for Dur\/Tre, also predicted response.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Our findings reveal regimen-specific systemic immune mechanisms in advanced HCC: Atez\/Bev amplifies monocyte\u2013NK cytotoxic axes, whereas Dur\/Tre enhances monocyte\u2013T cell inflammatory networks and TCR repertoire diversity. These insights highlight distinct predictive biomarkers and support regimen-tailored immunotherapy in HCC.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1136\/jitc-2025-013648","type":"journal-article","created":{"date-parts":[[2026,3,30]],"date-time":"2026-03-30T14:20:12Z","timestamp":1774880412000},"page":"e013648","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":3,"title":["Systemic immune profiling uncovers divergent mechanisms and predictive biomarkers of response to combination immunotherapies in hepatocellular carcinoma"],"prefix":"10.1136","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1668-0779","authenticated-orcid":false,"given":"Akira","family":"Nishio","sequence":"first","affiliation":[{"name":"Department of Gastroenterology and Hepatology, Graduate School of Medicine, The University of Osaka, Suita, Japan"},{"name":"Department of Gastroenterology and Hepatology, Japan Community Health Care 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