{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,3]],"date-time":"2026-10-03T03:44:06Z","timestamp":1790999046639,"version":"4.1.0"},"reference-count":34,"publisher":"BMJ","issue":"12","license":[{"start":{"date-parts":[[2025,12,1]],"date-time":"2025-12-01T00:00:00Z","timestamp":1764547200000},"content-version":"unspecified","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82394451"],"award-info":[{"award-number":["82394451"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Innovation and Technology Commission grant of Hong Kong SAR Government to State Key Laboratory of Liver Research","award":["ITC PD\/17-9"],"award-info":[{"award-number":["ITC PD\/17-9"]}]},{"name":"University Development Fund of The University of Hong Kong","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}]},{"name":"Research Grants Council of Hong Kong \u2013 Theme-based Research Scheme","award":["T12-716\/22R"],"award-info":[{"award-number":["T12-716\/22R"]}]},{"name":"The Hong Kong Scholars Program","award":["XJ2023053"],"award-info":[{"award-number":["XJ2023053"]}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["J Immunother Cancer"],"accepted":{"date-parts":[[2025,11,11]]},"published-print":{"date-parts":[[2025,12]]},"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Programmed cell death protein-1 (PD-1) blockade has shown promising clinical efficacy in hepatocellular carcinoma (HCC), yet the underlying immunological mechanisms governing response and resistance remain unclear. This study aimed to delineate the temporal and spatial dynamics of T-cell clonotypes and their relationship with pathological response in neoadjuvant PD-1 blockade therapy in HCC. By integrating T-cell receptor (TCR) repertoire analysis with transcriptomic profiling, we sought to elucidate the immune landscape alterations associated with treatment outcomes.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      We analyzed longitudinal, matched tumor and blood samples from our previous clinical trial (\n                      <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"clintrialgov\" xlink:href=\"NCT05471674\">NCT05471674<\/jats:ext-link>\n                      ), encompassing 114 specimens, including pre-nivolumab tumor biopsies, post-treatment resected tumors, adjacent non-tumorous livers, and peripheral blood collected before, after, and during follow-up from 19 treatment-na\u00efve HCC. TCR clonality, diversity, and transcriptomic signatures were assessed to characterize immune responses.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Elevated clonality of intratumoral TCR clonotypes (ITCs) post-treatment correlated with increased pathological tumor necrosis, predominantly driven by the most abundant top 1% ITCs. These dominant clonotypes occupied a significantly larger clonal space and demonstrated increased spatial sharing across tumor, non-tumorous liver, and peripheral blood compartments in nivolumab responders (nivo-Rs). Shared clonotypes were positively associated with tumor necrosis extent and cytolytic activity, suggesting active immune engagement. Post-treatment, shared clonotypes exhibited peripheral expansion and greater intratumoral dominance in nivo-Rs, whereas tumor unique intratumoral TCR clonotypes (ITCs) remained prevalent in non-responders (nivo-NRs). These divergent patterns were linked to higher chemokine expression within the tumor microenvironment of nivo-Rs and impaired human leukocyte antigen (HLA) class II antigen presentation in nivo-NRs, indicating distinct immune landscape configurations influencing therapeutic response.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Our findings demonstrate that the peripheral infiltration and expansion of high-frequency intratumoral T-cell clonotypes are critical drivers of pathological response to neoadjuvant PD-1 blockade in HCC, highlighting potential immune biomarkers and therapeutic targets to enhance immunotherapy efficacy.<\/jats:p>\n                  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