title: Cytotoxic CD4+T cells are correlated with better prognosis in Han Chinese grade II and grade III glioma subjects and are suppressed by PD-1 signaling.
abstract: OBJECTIVE
  Malignant gliomas are the most common tumors in the central nervous system with a poor prognosis. Recently, CD4+cytotoxic T cells (CTLs) are being increasingly recognized as possessing antitumor capacity. However, their presence, activity and regulation in glioma have not been investigated in detail.
  
  
  METHODS
  To examine this, 72 grade II and grade III Han Chinese glioma patients and 30 Han Chinese healthy controls were investigated.
  
  
  RESULTS
  We found that compared to healthy controls, glioma patients had significantly upregulated frequencies of circulating CD4+CTLs, identified by the expression of granzyme A (GzmA), granzyme B (GzmB) and/or perforin. The stimulated CD4+CTLs in grade II and grade III glioma patients also had less proliferative ability than those in healthy controls, a feature of suppression that progressed with tumor grade. The frequencies of GzmB-expressing circulating CD4+CTLs were directly associated with prognosis. We hypothesized that the programed death 1 (PD-1)/PD-ligand 1 (L1) interaction possibly contributed to the suppression of CD4+CTLs in grade II and grade III glioma, since an upregulation of PD-1 was observed on CD4+CTLs in glioma compared to those in the healthy individuals. Blockade of the PD-1/PD-L1 interaction with neutralizing antibodies significantly increased the proliferation and granzyme or perforin production by CD4+CTLs in grade II and grade III glioma patients.
  
  
  CONCLUSIONS
  These data suggest that the CD4+CTLs in grade II and grade III glioma patients contribute to antitumor immunity and could be suppressed by PD-1 signal transduction.
authors.affiliation: a 1 College of Humanities and Law, North China University of Technology , Beijing , China.
authors.forename: Jing
authors.initials: J
authors.lastname: Ge
authors.affiliation: b 2 Department of Respiratory and Renal Diseases, The 155th Central Hospital of PLA , Kaifeng , China.
authors.forename: Lina
authors.initials: L
authors.lastname: Zhao
authors.affiliation: c 3 Affiliated Bayi Brain Hospital, General Hospital of Beijing Military Command , Beijing , China.
authors.forename: Guanggang
authors.initials: G
authors.lastname: Li
authors.affiliation: d 4 Diaville Biomedical and Computational Research Centre , British Columbia , Canada.
authors.forename: Jason
authors.initials: J
authors.lastname: White
authors.affiliation: e 5 Department of Hematology & Oncology, The 155th Central Hospital of PLA/The Key Laboratory of Hematology of Kaifeng city , Kaifeng , China.
authors.forename: Zongchang
authors.initials: Z
authors.lastname: Song
authors.affiliation: f 6 Department of Psychology, Shandong Normal University , Jinan , China.
authors.forename: Zhifei
authors.initials: Z
authors.lastname: Wang
authors.affiliation: g 7 Department of Surgery, Linyi People's Hospital , Linyi , China.
authors.forename: Ludong
authors.initials: L
authors.lastname: Zhao
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000704:Analysis of Variance; D044466:Asian People / Q000208:ethnology; D001932:Brain Neoplasms / Q000175:diagnosis / Q000378:metabolism / Q000473:pathology; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism / Q000473:pathology*; D049109:Cell Proliferation / Q000502:physiology; D005260:Female; D005434:Flow Cytometry; D005910:Glioma / Q000175:diagnosis / Q000378:metabolism / Q000473:pathology; D053804:Granzymes / Q000378:metabolism; D006801:Humans; D008297:Male; D008875:Middle Aged; D054353:Perforin / Q000378:metabolism; D061026:Programmed Cell Death 1 Receptor / Q000378:metabolism*; D012720:Severity of Illness Index; D015398:Signal Transduction / Q000502:physiology*; D018709:Statistics, Nonparametric; D055815:Young Adult
chemical_list: C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor; D054353:Perforin; D053804:Granzymes
keywords: PD-1; cytotoxic CD4+ T cell; glioma