title: Human hepatocellular carcinoma-infiltrating CD4⁺CD69⁺Foxp3⁻ regulatory T cell suppresses T cell response via membrane-bound TGF-β1.
abstract: Tumors can recruit, induce, and expand regulatory T cells (Tregs) to suppress antitumor immune responses for survival and progression. The complicated tumor-related Treg subsets and their functional mechanisms are not fully addressed yet. We have previously identified a novel CD4⁺CD69⁺Foxp3⁻ Treg subset in tumor-bearing mice, which suppresses CD4 T cell response via membrane-bound transforming growth factor beta 1 (mTGF-β1) and then promotes tumor progression. In hepatocellular carcinoma patients, here, we identified tumor-infiltrating human CD4⁺CD69⁺ Tregs which represent ~67.2 % of tumor-infiltrating CD4 T cells that is significantly higher than conventional CD4⁺CD25⁺Foxp3⁺ Tregs. They expressed mTGF-β1, PD-1, and CTLA-4, but not CD25 or Foxp3, and only produced a little interleukin (IL)-10 and TGF-β1. More importantly, they significantly suppressed CD4 T cell response via mTGF-β1 in vitro. Furthermore, the percentage of these CD4⁺CD69⁺ Tregs in tumor tissue was significantly correlated with tumor progression, which is more pronounced at the late stage of cancer patients. Thus, we have identified a tumor-induced new population of human CD4⁺CD69⁺ Tregs in cancer patients with phenotype of CD25⁻Foxp3⁻mTGF-β1⁺CTLA-4⁺PD-1⁺, and these Tregs can suppress antitumor immune response via mTGF-β1. Our results not only enrich the family of Treg subsets, providing new mechanistic insight to tumor-induced immune suppression in human, but also suggest a potential target for cancer immunotherapy.
  
  
  CONCLUSIONS
  CD4⁺CD69⁺Foxp3⁻ regulatory T cells were identified in hepatocellular carcinoma patients. These Treg cells inhibit T cell response via membrane-bound TGF-β. The percentage of these cells was significantly correlated with tumor progression. The percentage of these cells was higher than conventional CD4⁺CD25⁺Foxp3⁺ Tregs. These Treg cells not only exist in tumor-bearing mice, but also in cancer patients.
authors.affiliation: National Key Laboratory of Medical Immunology & Institute of Immunology, Second Military Medical University, 800 Xiangyin Road, Shanghai, 200433, China.
authors.forename: Yanmei
authors.initials: Y
authors.lastname: Han
authors.forename: Yuan
authors.initials: Y
authors.lastname: Yang
authors.forename: Zhubo
authors.initials: Z
authors.lastname: Chen
authors.forename: Zhengping
authors.initials: Z
authors.lastname: Jiang
authors.forename: Yan
authors.initials: Y
authors.lastname: Gu
authors.forename: Yanfang
authors.initials: Y
authors.lastname: Liu
authors.forename: Sheng
authors.initials: S
authors.lastname: Xu
authors.forename: Chuan
authors.initials: C
authors.lastname: Lin
authors.forename: Zeya
authors.initials: Z
authors.lastname: Pan
authors.forename: Weiping
authors.initials: W
authors.lastname: Zhou
authors.forename: Xuetao
authors.initials: X
authors.lastname: Cao
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000818:Animals; D015703:Antigens, CD / Q000032:analysis / Q000276:immunology*; D000945:Antigens, Differentiation, T-Lymphocyte / Q000032:analysis / Q000276:immunology*; D015704:CD4 Antigens / Q000032:analysis / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D002478:Cells, Cultured; D005260:Female; D051858:Forkhead Transcription Factors / Q000032:analysis / Q000235:genetics; D017353:Gene Deletion; D006801:Humans; D037181:Lectins, C-Type / Q000032:analysis / Q000276:immunology*; D008099:Liver / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008113:Liver Neoplasms / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D008213:Lymphocyte Activation; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008875:Middle Aged; D053773:Transforming Growth Factor beta1 / Q000032:analysis / Q000276:immunology*; D055815:Young Adult; D000099192:CD69 Antigens
chemical_list: D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D015704:CD4 Antigens; D051858:Forkhead Transcription Factors; D037181:Lectins, C-Type; D053773:Transforming Growth Factor beta1; D000099192:CD69 Antigens; C418974:FOXP3 protein, human