title: DNA demethylating agent decitabine broadens the peripheral T cell receptor repertoire.
abstract: OBJECTIVE
  Decitabine, a promising epi-immunotherapeutic agent has shown clinical responses in solid tumor patients, while the anti-tumor mechanisms were unclear. We aimed to investigate the immunomodulatory effect of decitabine in peripheral T cells.
  
  
  METHODS
  We applied next-generation sequencing to investigate the complementarity-determining region 3 (CDR3) of the TCRβ gene, the diversity of which acts as the prerequisite for the host immune system to recognize the universal foreign antigens. We collected the peripheral blood mononuclear cells (PBMCs) from 4 patients, at baseline and after 2 cycles of low-dose decitabine therapy.
  
  
  RESULTS
  An increase of the unique productive sequences of the CDR3 of TCRβ was observed in all of the 4 patients after decitabine treatment, which was characterized by a lower abundance of expanded clones and increased TCR diversity compared with before decitabine treatment. Further analysis showed a tendency for CD4 T cells with an increased CD4/CD8 ratio in response to decitabine therapy. In addition, the genome-wide expression alterations confirmed the effects of decitabine on immune reconstitution, and the increase of TCR excision circles (TRECs) was validated.
  
  
  CONCLUSIONS
  The low-dose DNMT inhibitor decitabine broadens the peripheral T cell repertoire, providing a novel role for the epigenetic modifying agent in anti-tumor immune enhancement.
authors.affiliation: Department of Immunology, Institute of Basic Medical Science, PLA General Hospital, Beijing, 100853, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Nie
authors.affiliation: Department of Biological Therapy, PLA General Hospital, Beijing, 100853, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Immunology, Institute of Basic Medical Science, PLA General Hospital, Beijing, 100853, China.
authors.forename: Xiang
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Biological Therapy, PLA General Hospital, Beijing, 100853, China.
authors.forename: Meixia
authors.initials: M
authors.lastname: Chen
authors.affiliation: Department of Immunology, Institute of Basic Medical Science, PLA General Hospital, Beijing, 100853, China.
authors.forename: Chuanjie
authors.initials: C
authors.lastname: Liu
authors.affiliation: Department of Immunology, Institute of Basic Medical Science, PLA General Hospital, Beijing, 100853, China.|Department of Biological Therapy, PLA General Hospital, Beijing, 100853, China.
authors.forename: Weidong
authors.initials: W
authors.lastname: Han
mesh_terms: D000328:Adult; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology; D001374:Azacitidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology; D022801:Complementarity Determining Regions / Q000378:metabolism; D019175:DNA Methylation; D000077209:Decitabine; D044127:Epigenesis, Genetic; D005260:Female; D006801:Humans; D007167:Immunotherapy / Q000379:methods; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000276:immunology / Q000378:metabolism; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000378:metabolism*; D013601:T-Lymphocytes / Q000187:drug effects*
chemical_list: D000964:Antimetabolites, Antineoplastic; D000970:Antineoplastic Agents; D022801:Complementarity Determining Regions; D016693:Receptors, Antigen, T-Cell, alpha-beta; D000077209:Decitabine; D001374:Azacitidine
keywords: T cell receptor repertoire; decitabine; epigenetic therapy; pharmacometabonomics; solid tumor