DNA demethylating agent decitabine broadens the peripheral T cell receptor repertoire

// Jing Nie 1 , Yan Zhang 2 , Xiang Li 1 , Meixia Chen 2 , Chuanjie Liu 1 , Weidong Han 1, 2 1 Department of Immunology, Institute of Basic Medical Science, PLA General Hospital, Beijing, 100853, China 2 Department of Biological Therapy, PLA General Hospital, Beijing, 100853, China Correspondence to: Weidong Han, email: hanwdrsw@sina.com Jing Nie, email: nnjj2002@163.com Keywords: T cell receptor repertoire, pharmacometabonomics, decitabine, epigenetic therapy, solid tumor Received: December 28, 2015 Accepted: April 28, 2016 Published: May 13, 2016 ABSTRACT Purpose: 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. Experimental design: 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.