{"doi":"10.1111/apm.12704","title":"HBV‐specific CD4+ cytotoxic T cells in hepatocellular carcinoma are less cytolytic toward tumor cells and suppress CD8+ T cell‐mediated antitumor immunity","abstract":"In East Asia and sub‐Saharan Africa, chronic infection is the main cause of the development of hepatocellular carcinoma, an aggressive cancer with low survival rate. Cytotoxic T cell‐based immunotherapy is a promising treatment strategy. Here, we investigated the possibility of using HBV‐specific CD4+ cytotoxic T cells to eliminate tumor cells. The naturally occurring HBV‐specific cytotoxic CD4+ and CD8+ T cells were identified by HBV peptide pool stimulation. We found that in HBV‐induced hepatocellular carcinoma patients, the HBV‐specific cytotoxic CD4+ T cells and cytotoxic CD8+ T cells were present at similar numbers. But compared to the CD8+ cytotoxic T cells, the CD4+ cytotoxic T cells secreted less cytolytic factors granzyme A (GzmA) and granzyme B (GzmB), and were less effective at eliminating tumor cells. In addition, despite being able to secrete cytolytic factors, CD4+ T cells suppressed the cytotoxicity mediated by CD8+ T cells, even when CD4+CD25+ regulator T cells were absent. Interestingly, we found that interleukin 10 (IL‐10)‐secreting Tr1 cells were enriched in the cytotoxic CD4+ T cells. Neutralization of IL‐10 abrogated the suppression of CD8+ T cells by CD4+CD25− T cells. Neither the frequency nor the absolute number of HBV‐specific CD4+ cytotoxic T cells were correlated with the clinical outcome of advanced stage hepatocellular carcinoma patients. Together, this study demonstrated that in HBV‐related hepatocellular carcinoma, CD4+ T cell‐mediated cytotoxicity was present naturally in the host and had the potential to exert antitumor immunity, but its capacity was limited and was associated with immunoregulatory properties.","journal":"APMIS","year":2017,"id":662900,"datarank":0.4887144807032224,"base_score":3.258096538021482,"endowment":3.258096538021482,"self_citation_contribution":0.4887144807032224,"citation_network_contribution":0.0,"self_endowment_contribution":0.4887144807032224,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":25,"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":1730640,"name":"Shoumei Zhen","orcid":null,"position":1,"is_corresponding":false},{"id":226360,"name":"Bin Song","orcid":"0000-0002-9528-3837","position":2,"is_corresponding":false},{"id":157192,"name":"Fanzhi Meng","orcid":null,"position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"title":"HBV‐specific CD4+ cytotoxic T cells in hepatocellular carcinoma are less cytolytic toward tumor cells and suppress CD8+ T cell‐mediated antitumor immunity","abstract":"In East Asia and sub‐Saharan Africa, chronic infection is the main cause of the development of hepatocellular carcinoma, an aggressive cancer with low survival rate. Cytotoxic T cell‐based immunotherapy is a promising treatment strategy. Here, we investigated the possibility of using HBV‐specific CD4+ cytotoxic T cells to eliminate tumor cells. The naturally occurring HBV‐specific cytotoxic CD4+ and CD8+ T cells were identified by HBV peptide pool stimulation. We found that in HBV‐induced hepatocellular carcinoma patients, the HBV‐specific cytotoxic CD4+ T cells and cytotoxic CD8+ T cells were present at similar numbers. But compared to the CD8+ cytotoxic T cells, the CD4+ cytotoxic T cells secreted less cytolytic factors granzyme A (GzmA) and granzyme B (GzmB), and were less effective at eliminating tumor cells. In addition, despite being able to secrete cytolytic factors, CD4+ T cells suppressed the cytotoxicity mediated by CD8+ T cells, even when CD4+CD25+ regulator T cells were absent. Interestingly, we found that interleukin 10 (IL‐10)‐secreting Tr1 cells were enriched in the cytotoxic CD4+ T cells. Neutralization of IL‐10 abrogated the suppression of CD8+ T cells by CD4+CD25− T cells. Neither the frequency nor the absolute number of HBV‐specific CD4+ cytotoxic T cells were correlated with the clinical outcome of advanced stage hepatocellular carcinoma patients. Together, this study demonstrated that in HBV‐related hepatocellular carcinoma, CD4+ T cell‐mediated cytotoxicity was present naturally in the host and had the potential to exert antitumor immunity, but its capacity was limited and was associated with immunoregulatory properties.","is_dataset_classified":null,"base_score":3.258096538021482,"endowment":3.258096538021482,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"28493520","pmcid":null,"openalex_id":"https://openalex.org/W2613941137","authors":[],"funders":[],"total_grants":0,"fwci":2.4553,"citation_percentile":0.89318128,"influential_citations":0,"citation_trend":[{"year":2018,"count":2},{"year":2019,"count":2},{"year":2020,"count":5},{"year":2021,"count":2},{"year":2022,"count":5},{"year":2023,"count":3},{"year":2024,"count":4},{"year":2025,"count":2}],"oa_status":"closed","license":"http://onlinelibrary.wiley.com/termsAndConditions#vor","oa_locations":[{"url":"https://api.wiley.com/onlinelibrary/tdm/v1/articles/10.1111%2Fapm.12704","host_type":"publisher"},{"url":"https://onlinelibrary.wiley.com/doi/pdf/10.1111/apm.12704","host_type":"publisher"},{"url":"https://doi.org/10.1111/apm.12704","host_type":"journal"},{"url":"https://pubmed.ncbi.nlm.nih.gov/28493520","host_type":"repository"}],"fields_of_study":["Hepatitis B Virus Studies","Immunotherapy and Immune Responses","Cancer Immunotherapy and Biomarkers","Africa South of the Sahara","CD4-Positive T-Lymphocytes","CD8-Positive T-Lymphocytes","Carcinoma, Hepatocellular","Cohort Studies","Asia, Eastern","Female","Granzymes","Hepatitis B virus","Hepatitis B, Chronic","Humans","Immune Tolerance","Liver Neoplasms","Male","Middle Aged","T-Lymphocytes, Cytotoxic"],"mesh_terms":["Asia, Eastern","Female","Hepatitis B virus","Carcinoma, Hepatocellular","Humans","Immune Tolerance","Liver Neoplasms","Male","Middle Aged","T-Lymphocytes, Cytotoxic","Cohort Studies","CD4-Positive T-Lymphocytes","Africa South of the Sahara","CD8-Positive T-Lymphocytes","Hepatitis B, Chronic","Granzymes"],"keywords":["Cytotoxic T cell","Granzyme B","IL-2 receptor","Interleukin 21","Granzyme","CD8","Biology","Cancer research","Immunology","Immunotherapy","T cell","Immune system","Perforin","In vitro","Biochemistry","Hepatitis B virus","Hepatocellular carcinoma","Cytotoxic T cells"],"sdg_mappings":[{"sdg_number":0,"sdg_label":"Good health and well-being"}],"linked_datasets":[],"clinical_trials":[],"software_tools":[],"database_accessions":[],"source":"live","citation_network_status":"fetched"},"created_at":"2026-08-12T18:07:13.693867Z","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":[]}