Abstract
PurposeDecitabine, 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 designWe 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.ResultsAn 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.ConclusionsThe 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.
Highlights
B and T lymphocytes possess the capacity to recognize foreign molecules through various antigenbinding receptors (B cell receptor and T cell receptor [TCR])
An increase of the unique productive sequences of the complementarity-determining region 3 (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
The genome-wide expression alterations confirmed the effects of decitabine on immune reconstitution, and the increase of TCR excision circles (TRECs) was validated
Summary
B and T lymphocytes possess the capacity to recognize foreign molecules through various antigenbinding receptors (B cell receptor and T cell receptor [TCR]). The diversity of immune repertoires is created via recombination of variable (V), diversity (D), and joining (J) gene segments, which form the antigen-binding variable region. Nucleotide deletion or insertion at gene junction sites contributes to the substantial TCR diversity. As many as 1011 different TCRs can be generated during the somatic recombination process in human T cells [1]. The antigenic specificity of T lymphocytes is primarily determined by the sequences in the hypervariable CDR3 (complementarity-determining region 3) of the TCR. The CDR3 sequences have been viewed as the natural identifier of T cell clonality
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