title: Functionally distinct subsets of CD4⁺ regulatory T cells in patients with laryngeal squamous cell carcinoma are indicative of immune deregulation and disease progression.
abstract: CD4+ regulatory T cells (Tregs) mediate immune tolerance in laryngeal squamous cell carcinoma (LSCC). However, Tregs are functionally heterogeneous. Recently, we reported that three distinct Treg subsets (resting Tregs, activated Tregs and cytokine-secreting CD45RA-Foxp3lowCD4+ T cells) vary in the peripheral circulation of patients with head and neck squamous cell carcinoma (HNSCC); however, the potential implication of these Treg subsets in LSCC immunity is unclear. Here, we report that activated Tregs and cytokine‑secreting CD45RA-Foxp3lowCD4+ T cells were increased in LSCC patients compared with healthy donors (HD) (p<0.001, p<0.001), whereas resting Tregs were decreased (p<0.001). Activated Tregs inhibited the proliferation of CD4+CD25- T cells (p<0.001) and secreted lower levels of interleukin-2 (p<0.001), interferon-γ (p<0.001) and tumor necrosis factor-α (p<0.001) compared with the cytokine-secreting CD45RA-Foxp3lowCD4+ T cells. Importantly, activated Treg prevalence was correlated with tumor stage (p=0.001) and nodal status (p=0.007). The prevalence of naïve CD4+ (p<0.001), naïve CD8+ (p=0.002), and Th1 T-cell subsets (p<0.001, p<0.001) was decreased in the LSCC patients. In conclusion, our findings showed that activated Tregs with suppressive activity are a distinct subset of Tregs in LSCC, and correlate with disease progression. Several immune system abnormalities in LSCC patients are represented by expansion of functionally activated Tregs, both in the circulation and tumor microenvironment along with decreased frequencies of naïve T-cell populations and Th1-cell populations.
authors.affiliation: Department of Otorhinolaryngology Head and Neck Surgery, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, P.R. China.
authors.forename: Wei
authors.initials: W
authors.lastname: Sun
authors.affiliation: Department of Otorhinolaryngology Head and Neck Surgery, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, P.R. China.
authors.forename: Wei-Jin
authors.initials: WJ
authors.lastname: Li
authors.affiliation: Department of Otorhinolaryngology Head and Neck Surgery, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, P.R. China.
authors.forename: Qing-Ling
authors.initials: QL
authors.lastname: Fu
authors.affiliation: Institute of Immunology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, P.R. China.
authors.forename: Chang-You
authors.initials: CY
authors.lastname: Wu
authors.affiliation: Department of Otorhinolaryngology Head and Neck Surgery, University of Minnesota, Minneapolis, MN, USA.
authors.forename: Ji-Zhen
authors.initials: JZ
authors.lastname: Lin
authors.affiliation: Department of Otorhinolaryngology Head and Neck Surgery, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, P.R. China.
authors.forename: Xiao-Lin
authors.initials: XL
authors.lastname: Zhu
authors.affiliation: Department of Otorhinolaryngology Head and Neck Surgery, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, P.R. China.
authors.forename: Wei-Jian
authors.initials: WJ
authors.lastname: Hou
authors.affiliation: Department of Otorhinolaryngology Head and Neck Surgery, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, P.R. China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Wei
authors.affiliation: Department of Otorhinolaryngology Head and Neck Surgery, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, P.R. China.
authors.forename: Yi-Hui
authors.initials: YH
authors.lastname: Wen
authors.affiliation: Department of Otorhinolaryngology Head and Neck Surgery, The First Hospital of Foshan, Foshan, Guangdong, P.R. China.
authors.forename: Yue-Jian
authors.initials: YJ
authors.lastname: Wang
authors.affiliation: Department of Otorhinolaryngology Head and Neck Surgery, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, P.R. China.
authors.forename: Wei-Ping
authors.initials: WP
authors.lastname: Wen
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D016022:Case-Control Studies; D018450:Disease Progression; D005260:Female; D051858:Forkhead Transcription Factors / Q000378:metabolism; D006801:Humans; D053645:Interleukin-2 Receptor alpha Subunit / Q000378:metabolism; D007822:Laryngeal Neoplasms / Q000276:immunology* / Q000473:pathology; D017493:Leukocyte Common Antigens / Q000378:metabolism; D016131:Lymphocyte Subsets / Q000276:immunology; D008297:Male; D008875:Middle Aged; D018307:Neoplasms, Squamous Cell / Q000276:immunology* / Q000473:pathology; D012016:Reference Values; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism; D018417:Th1 Cells / Q000276:immunology
chemical_list: C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; C508017:IL2RA protein, human; D053645:Interleukin-2 Receptor alpha Subunit; D017493:Leukocyte Common Antigens