DNA demethylating agent decitabine broadens the peripheral T cell receptor repertoire
Jing Nie1, Yan Zhang2, Xiang Li1
1Department of Immunology, Institute of Basic Medical Science, PLA General Hospital, Beijing, 100853, China.
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.
Insights
Low-dose decitabine therapy broadens the peripheral T cell repertoire by increasing T cell receptor diversity. This epigenetic modification enhances the immune system
Area of Science:
- Immunology
- Epigenetics
- Oncology
Background:
- Decitabine, an epi-immunotherapeutic agent, shows clinical responses in solid tumors, but its anti-tumor mechanisms remain unclear.
- Investigating decitabine's immunomodulatory effects is crucial for understanding its therapeutic potential in cancer.
Purpose of the Study:
- To investigate the immunomodulatory effect of decitabine on peripheral T cells in solid tumor patients.
- To elucidate the anti-tumor mechanisms of decitabine through its impact on the T cell repertoire.
Main Methods:
- Applied next-generation sequencing to analyze the complementarity-determining region 3 (CDR3) of the TCRβ gene in peripheral blood mononuclear cells (PBMCs).
- Collected PBMCs from 4 solid tumor patients at baseline and after 2 cycles of low-dose decitabine therapy.
- Analyzed T cell receptor (TCR) diversity, CD4/CD8 ratio, and TCR excision circles (TRECs).
Main Results:
- Observed an increase in unique productive sequences of the TCRβ CDR3 in all patients post-decitabine treatment.
- Decitabine treatment led to decreased abundance of expanded clones and increased TCR diversity.
- Noted a tendency for increased CD4 T cells (higher CD4/CD8 ratio) and validated an increase in TRECs, confirming immune reconstitution.
Conclusions:
- Low-dose decitabine broadens the peripheral T cell repertoire, enhancing anti-tumor immunity.
- Decitabine acts as an epigenetic modifying agent with a novel role in immune enhancement against solid tumors.
