{"doi":"10.1002/hep.30881","title":"4‐1BB Delineates Distinct Activation Status of Exhausted Tumor‐Infiltrating CD8+ T Cells in Hepatocellular Carcinoma","abstract":"<jats:sec>\n            <jats:title>Background and Aims</jats:title>\n            <jats:p>Targeting costimulatory receptors with agonistic antibodies is a promising cancer immunotherapy option. We aimed to investigate costimulatory receptor expression, particularly 4‐1BB (CD137 or tumor necrosis factor receptor superfamily member 9), on tumor‐infiltrating CD8<jats:sup>+</jats:sup> T cells (CD8<jats:sup>+</jats:sup> tumor‐infiltrating lymphocytes [TILs]) and its association with distinct T‐cell activation features among exhausted CD8<jats:sup>+</jats:sup> TILs in hepatocellular carcinoma (HCC).</jats:p>\n          </jats:sec>\n          <jats:sec>\n            <jats:title>Approach and Results</jats:title>\n            <jats:p>Tumor tissues, adjacent nontumor tissues, and peripheral blood were collected from HCC patients undergoing surgical resection (n = 79). Lymphocytes were isolated and used for multicolor flow cytometry, RNA‐sequencing, and <jats:italic toggle=\"yes\">in vitro</jats:italic> functional restoration assays. Among the examined costimulatory receptors, 4‐1BB was most prominently expressed on CD8<jats:sup>+</jats:sup> TILs. 4‐1BB expression was almost exclusively detected on CD8<jats:sup>+</jats:sup> T cells in the tumor—especially on programmed death 1 (PD‐1)<jats:sup>high</jats:sup> cells and not PD‐1<jats:sup>int</jats:sup> and PD‐1<jats:sup>neg</jats:sup> cells. Compared to PD‐1<jats:sup>int</jats:sup> and 4‐1BB<jats:sup>neg</jats:sup>PD‐1<jats:sup>high</jats:sup> CD8<jats:sup>+</jats:sup> TILs, 4‐1BB<jats:sup>pos</jats:sup>PD‐1<jats:sup>high</jats:sup> CD8<jats:sup>+</jats:sup> TILs exhibited higher levels of tumor reactivity and T‐cell activation markers and significant enrichment for T‐cell activation gene signatures. Per‐patient analysis revealed positive correlations between percentages of 4‐1BB<jats:sup>pos</jats:sup> cells among CD8<jats:sup>+</jats:sup> TILs and levels of parameters of tumor reactivity and T‐cell activation. Among highly exhausted PD‐1<jats:sup>high</jats:sup> CD8<jats:sup>+</jats:sup> TILs, 4‐1BB<jats:sup>pos</jats:sup> cells harbored higher proportions of cells with proliferative and reinvigoration potential. Our 4‐1BB–related gene signature predicted survival outcomes of HCC patients in the The Cancer Genome Atlas cohort. 4‐1BB agonistic antibodies enhanced the function of CD8<jats:sup>+</jats:sup> TILs and further enhanced the anti‐PD‐1–mediated reinvigoration of CD8<jats:sup>+</jats:sup> TILs, especially in cases showing high levels of T‐cell activation.</jats:p>\n          </jats:sec>\n          <jats:sec>\n            <jats:title>Conclusion</jats:title>\n            <jats:p>4‐1BB expression on CD8<jats:sup>+</jats:sup> TILs represents a distinct activation state among highly exhausted CD8<jats:sup>+</jats:sup> T cells in HCC. 4‐1BB costimulation with agonistic antibodies may be a promising strategy for treating HCCs exhibiting prominent T‐cell activation.</jats:p>\n          </jats:sec>","journal":"Hepatology","year":2020,"id":669257,"datarank":0.6937459219926407,"base_score":4.624972813284271,"endowment":4.624972813284271,"self_citation_contribution":0.6937459219926407,"citation_network_contribution":0.0,"self_endowment_contribution":0.6937459219926407,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":101,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":null,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":984250,"name":"Seongyeol Park","orcid":"0000-0002-9236-5853","position":1,"is_corresponding":false},{"id":1747862,"name":"Seongju Jeong","orcid":null,"position":2,"is_corresponding":false},{"id":1747863,"name":"Yong Joon Lee","orcid":null,"position":3,"is_corresponding":false},{"id":1565761,"name":"Hoyoung Lee","orcid":"0000-0003-1266-7147","position":4,"is_corresponding":false},{"id":1747864,"name":"Chang Gon Kim","orcid":null,"position":5,"is_corresponding":false},{"id":1281732,"name":"Kyung Hwan Kim","orcid":"0000-0002-0482-9786","position":6,"is_corresponding":false},{"id":262920,"name":"Seung‐Mo Hong","orcid":"0000-0002-8888-6007","position":7,"is_corresponding":false},{"id":845850,"name":"Jung‐Yun Lee","orcid":"0000-0001-7948-1350","position":8,"is_corresponding":false},{"id":175555,"name":"Sunghoon Kim","orcid":null,"position":9,"is_corresponding":false},{"id":1018828,"name":"Hong Kwan Kim","orcid":null,"position":10,"is_corresponding":false},{"id":1747865,"name":"Byung Soh Min","orcid":null,"position":11,"is_corresponding":false},{"id":345388,"name":"Jong Hee Chang","orcid":"0000-0003-1509-9800","position":12,"is_corresponding":false},{"id":13625,"name":"Young Seok Ju","orcid":"0000-0002-5514-4189","position":13,"is_corresponding":false},{"id":666400,"name":"Eui‐Cheol Shin","orcid":"0000-0002-6308-9503","position":14,"is_corresponding":false},{"id":1747866,"name":"Gi‐Won Song","orcid":null,"position":15,"is_corresponding":false},{"id":152192,"name":"Shin Hwang","orcid":null,"position":16,"is_corresponding":false},{"id":1039063,"name":"Su‐Hyung Park","orcid":"0000-0001-6363-7736","position":17,"is_corresponding":false},{"id":1747861,"name":"Hyung‐Don Kim","orcid":null,"position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"title":"4‐1BB Delineates Distinct Activation Status of Exhausted Tumor‐Infiltrating CD8+ T Cells in Hepatocellular Carcinoma","abstract":"<jats:sec>\n            <jats:title>Background and Aims</jats:title>\n            <jats:p>Targeting costimulatory receptors with agonistic antibodies is a promising cancer immunotherapy option. We aimed to investigate costimulatory receptor expression, particularly 4‐1BB (CD137 or tumor necrosis factor receptor superfamily member 9), on tumor‐infiltrating CD8<jats:sup>+</jats:sup> T cells (CD8<jats:sup>+</jats:sup> tumor‐infiltrating lymphocytes [TILs]) and its association with distinct T‐cell activation features among exhausted CD8<jats:sup>+</jats:sup> TILs in hepatocellular carcinoma (HCC).</jats:p>\n          </jats:sec>\n          <jats:sec>\n            <jats:title>Approach and Results</jats:title>\n            <jats:p>Tumor tissues, adjacent nontumor tissues, and peripheral blood were collected from HCC patients undergoing surgical resection (n = 79). Lymphocytes were isolated and used for multicolor flow cytometry, RNA‐sequencing, and <jats:italic toggle=\"yes\">in vitro</jats:italic> functional restoration assays. Among the examined costimulatory receptors, 4‐1BB was most prominently expressed on CD8<jats:sup>+</jats:sup> TILs. 4‐1BB expression was almost exclusively detected on CD8<jats:sup>+</jats:sup> T cells in the tumor—especially on programmed death 1 (PD‐1)<jats:sup>high</jats:sup> cells and not PD‐1<jats:sup>int</jats:sup> and PD‐1<jats:sup>neg</jats:sup> cells. Compared to PD‐1<jats:sup>int</jats:sup> and 4‐1BB<jats:sup>neg</jats:sup>PD‐1<jats:sup>high</jats:sup> CD8<jats:sup>+</jats:sup> TILs, 4‐1BB<jats:sup>pos</jats:sup>PD‐1<jats:sup>high</jats:sup> CD8<jats:sup>+</jats:sup> TILs exhibited higher levels of tumor reactivity and T‐cell activation markers and significant enrichment for T‐cell activation gene signatures. Per‐patient analysis revealed positive correlations between percentages of 4‐1BB<jats:sup>pos</jats:sup> cells among CD8<jats:sup>+</jats:sup> TILs and levels of parameters of tumor reactivity and T‐cell activation. Among highly exhausted PD‐1<jats:sup>high</jats:sup> CD8<jats:sup>+</jats:sup> TILs, 4‐1BB<jats:sup>pos</jats:sup> cells harbored higher proportions of cells with proliferative and reinvigoration potential. Our 4‐1BB–related gene signature predicted survival outcomes of HCC patients in the The Cancer Genome Atlas cohort. 4‐1BB agonistic antibodies enhanced the function of CD8<jats:sup>+</jats:sup> TILs and further enhanced the anti‐PD‐1–mediated reinvigoration of CD8<jats:sup>+</jats:sup> TILs, especially in cases showing high levels of T‐cell activation.</jats:p>\n          </jats:sec>\n          <jats:sec>\n            <jats:title>Conclusion</jats:title>\n            <jats:p>4‐1BB expression on CD8<jats:sup>+</jats:sup> TILs represents a distinct activation state among highly exhausted CD8<jats:sup>+</jats:sup> T cells in HCC. 4‐1BB costimulation with agonistic antibodies may be a promising strategy for treating HCCs exhibiting prominent T‐cell activation.</jats:p>\n          </jats:sec>","is_dataset_classified":null,"base_score":4.624972813284271,"endowment":4.624972813284271,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"31353502","pmcid":"PMC7154753","openalex_id":"https://openalex.org/W2965932258","authors":[],"funders":[{"funder_name":"National Research Foundation of Korea","grant_id":"NRF‐2016H1A2A1906766","title":null}],"total_grants":1,"fwci":4.2891,"citation_percentile":0.95668746,"influential_citations":0,"citation_trend":[{"year":2019,"count":1},{"year":2020,"count":11},{"year":2021,"count":14},{"year":2022,"count":22},{"year":2023,"count":23},{"year":2024,"count":12},{"year":2025,"count":8},{"year":2026,"count":10}],"oa_status":"hybrid","license":"cc-by-nc","oa_locations":[{"url":"https://aasldpubs.onlinelibrary.wiley.com/doi/pdfdirect/10.1002/hep.30881","host_type":"journal"},{"url":"https://aasldpubs.onlinelibrary.wiley.com/doi/pdfdirect/10.1002/hep.30881","host_type":"publisher"},{"url":"https://onlinelibrary.wiley.com/doi/pdf/10.1002/hep.30881","host_type":"publisher"},{"url":"https://onlinelibrary.wiley.com/doi/full-xml/10.1002/hep.30881","host_type":"publisher"},{"url":"https://journals.lww.com/10.1002/hep.30881","host_type":"publisher"},{"url":"https://doi.org/10.1002/hep.30881","host_type":"journal"},{"url":"https://pubmed.ncbi.nlm.nih.gov/31353502","host_type":"repository"},{"url":"https://www.ncbi.nlm.nih.gov/pmc/articles/7154753","host_type":"repository"},{"url":"https://escholarship.org/uc/item/0n01x88j","host_type":"repository"},{"url":"https://ir.ymlib.yonsei.ac.kr/handle/22282913/175624","host_type":"repository"},{"url":"https://europepmc.org/articles/PMC7154753","host_type":"Europe_PMC"},{"url":"https://europepmc.org/articles/PMC7154753?pdf=render","host_type":"Europe_PMC"}],"fields_of_study":["Cancer Immunotherapy and Biomarkers","CAR-T cell therapy research","Immune Cell Function and Interaction","Aged","CD8-Positive T-Lymphocytes","Carcinoma, Hepatocellular","Female","Humans","Liver Neoplasms","Lymphocyte Activation","Lymphocytes, Tumor-Infiltrating","Male","Middle Aged","Programmed Cell Death 1 Receptor","Tumor Necrosis Factor Receptor Superfamily, Member 9"],"mesh_terms":["Aged","Female","Carcinoma, Hepatocellular","Humans","Liver Neoplasms","Lymphocyte Activation","Male","Middle Aged","Lymphocytes, Tumor-Infiltrating","CD8-Positive T-Lymphocytes","Tumor Necrosis Factor Receptor Superfamily, Member 9","Programmed Cell Death 1 Receptor"],"keywords":["Tumor-infiltrating lymphocytes","CD8","CD137","Immunotherapy","Cancer research","Cytotoxic T cell","Biology","T cell","Flow cytometry","Immunology","Immune system","In vitro"],"sdg_mappings":[{"sdg_number":0,"sdg_label":"Life in Land"}],"linked_datasets":[],"clinical_trials":[],"software_tools":[],"database_accessions":[{"name":"geo"},{"name":"doi"}],"source":"live","citation_network_status":"fetched"},"created_at":"2026-08-14T14:46:13.579628Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}