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Selective depletion of regulatory T cell subsets by docetaxel treatment in patients with nonsmall cell lung cancer.

Li JY, Duan XF, Wang LP, Xu YJ, Huang L, Zhang TF, Liu JY, Li F, Zhang Z, Yue DL, Wang F, Zhang B, Zhang Y - J Immunol Res (2014)

Bottom Line: Treg cells, specifically activated Treg cell subset, significantly increased in patients with NSCLC.In vitro assay showed that docetaxel reduced all three subsets of Treg cells.More importantly, we found docetaxel-based chemotherapy significantly decreased all three Treg subsets after 4 cycles of treatment in 17 NSCLC patients.

View Article: PubMed Central - PubMed

Affiliation: Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China ; Biotherapy Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China.

ABSTRACT
Regulatory T (Treg) cells are potent suppressors that maintain immune homeostasis. Accumulation of Treg can inhibit effective immune responses in cancer patients, leading to tumor development and progression. Despite direct cytotoxicity, several chemotherapeutic drugs have been reported to deplete Treg cells for better prognosis for cancer patients. Treg cells are a heterogenous population with at least three different subsets, nonsuppressive, resting, and activated Treg cells. However, the characteristics of Treg cell subsets in lung cancer patients and how chemotherapy affects Treg cells remain elusive. In this study, we first analyzed Treg cell subsets in peripheral blood samples from 40 nonsmall cell lung cancer (NSCLC) patients and 20 healthy donors. Treg cells, specifically activated Treg cell subset, significantly increased in patients with NSCLC. Compared to nonsuppressive Treg cells, activated Treg cells expressed higher level of CD39 and predominantly produced inhibitory cytokines. In vitro assay showed that docetaxel reduced all three subsets of Treg cells. More importantly, we found docetaxel-based chemotherapy significantly decreased all three Treg subsets after 4 cycles of treatment in 17 NSCLC patients. Taken together, this study revealed dynamic changes of various Treg cell subsets in NSCLC patients before and after chemotherapy, providing activated Treg cells as a potential target for chemotherapy.

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The three Treg subsets reduced after being treated with docetaxel in vitro. (a) PBMCs from NSCLC patients were staining with CD25 and Foxp3 antibody and analyzed by flow cytometry. (b) The peripheral blood of NSCLC patients was collected and CD4+CD25+ T cells were isolated by flow cytometric sorting. Three Treg subsets were defined with CD4+CD45RA−CD25hi (aTreg) cells, CD4+CD45RA−CD25lo (non-Treg) cells, and CD4+CD45RA+CD25lo (rTreg) cells. The differences of three subsets with or without docetaxel were analyzed. *P < 0.05; **P < 0.01 by paired t-test.
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fig4: The three Treg subsets reduced after being treated with docetaxel in vitro. (a) PBMCs from NSCLC patients were staining with CD25 and Foxp3 antibody and analyzed by flow cytometry. (b) The peripheral blood of NSCLC patients was collected and CD4+CD25+ T cells were isolated by flow cytometric sorting. Three Treg subsets were defined with CD4+CD45RA−CD25hi (aTreg) cells, CD4+CD45RA−CD25lo (non-Treg) cells, and CD4+CD45RA+CD25lo (rTreg) cells. The differences of three subsets with or without docetaxel were analyzed. *P < 0.05; **P < 0.01 by paired t-test.

Mentions: Previous studies have shown that docetaxel induced tumor cell death and also increased the number of CD4+ and CD8+ T cells [24]. We investigated if docetaxel had different effects on each Treg subset. To address this issue, we treated purified CD4+CD25+ T cells derived PBMCs from NSCLC patients with docetaxel in vitro. Because the degree of Foxp3 was proportional to CD25 expression (Figure 4(a)), we isolated and defined aTreg, rTreg, and non-Treg cells as CD4+CD45RA−CD25hi, CD4+CD45RA+CD25lo, and CD4+CD45RA−CD25lo T cells. Three subsets of Treg cells were all decreased after docetaxel treatment. More interestingly, aTreg cells secreted more INF-γ and less TGF-β after docetaxel treatment (P < 0.05, Figure 4(b)). But there were no significant differences for cytokine production in rTreg and non-Treg cells after docetaxel treatment.


Selective depletion of regulatory T cell subsets by docetaxel treatment in patients with nonsmall cell lung cancer.

Li JY, Duan XF, Wang LP, Xu YJ, Huang L, Zhang TF, Liu JY, Li F, Zhang Z, Yue DL, Wang F, Zhang B, Zhang Y - J Immunol Res (2014)

The three Treg subsets reduced after being treated with docetaxel in vitro. (a) PBMCs from NSCLC patients were staining with CD25 and Foxp3 antibody and analyzed by flow cytometry. (b) The peripheral blood of NSCLC patients was collected and CD4+CD25+ T cells were isolated by flow cytometric sorting. Three Treg subsets were defined with CD4+CD45RA−CD25hi (aTreg) cells, CD4+CD45RA−CD25lo (non-Treg) cells, and CD4+CD45RA+CD25lo (rTreg) cells. The differences of three subsets with or without docetaxel were analyzed. *P < 0.05; **P < 0.01 by paired t-test.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4020463&req=5

fig4: The three Treg subsets reduced after being treated with docetaxel in vitro. (a) PBMCs from NSCLC patients were staining with CD25 and Foxp3 antibody and analyzed by flow cytometry. (b) The peripheral blood of NSCLC patients was collected and CD4+CD25+ T cells were isolated by flow cytometric sorting. Three Treg subsets were defined with CD4+CD45RA−CD25hi (aTreg) cells, CD4+CD45RA−CD25lo (non-Treg) cells, and CD4+CD45RA+CD25lo (rTreg) cells. The differences of three subsets with or without docetaxel were analyzed. *P < 0.05; **P < 0.01 by paired t-test.
Mentions: Previous studies have shown that docetaxel induced tumor cell death and also increased the number of CD4+ and CD8+ T cells [24]. We investigated if docetaxel had different effects on each Treg subset. To address this issue, we treated purified CD4+CD25+ T cells derived PBMCs from NSCLC patients with docetaxel in vitro. Because the degree of Foxp3 was proportional to CD25 expression (Figure 4(a)), we isolated and defined aTreg, rTreg, and non-Treg cells as CD4+CD45RA−CD25hi, CD4+CD45RA+CD25lo, and CD4+CD45RA−CD25lo T cells. Three subsets of Treg cells were all decreased after docetaxel treatment. More interestingly, aTreg cells secreted more INF-γ and less TGF-β after docetaxel treatment (P < 0.05, Figure 4(b)). But there were no significant differences for cytokine production in rTreg and non-Treg cells after docetaxel treatment.

Bottom Line: Treg cells, specifically activated Treg cell subset, significantly increased in patients with NSCLC.In vitro assay showed that docetaxel reduced all three subsets of Treg cells.More importantly, we found docetaxel-based chemotherapy significantly decreased all three Treg subsets after 4 cycles of treatment in 17 NSCLC patients.

View Article: PubMed Central - PubMed

Affiliation: Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China ; Biotherapy Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China.

ABSTRACT
Regulatory T (Treg) cells are potent suppressors that maintain immune homeostasis. Accumulation of Treg can inhibit effective immune responses in cancer patients, leading to tumor development and progression. Despite direct cytotoxicity, several chemotherapeutic drugs have been reported to deplete Treg cells for better prognosis for cancer patients. Treg cells are a heterogenous population with at least three different subsets, nonsuppressive, resting, and activated Treg cells. However, the characteristics of Treg cell subsets in lung cancer patients and how chemotherapy affects Treg cells remain elusive. In this study, we first analyzed Treg cell subsets in peripheral blood samples from 40 nonsmall cell lung cancer (NSCLC) patients and 20 healthy donors. Treg cells, specifically activated Treg cell subset, significantly increased in patients with NSCLC. Compared to nonsuppressive Treg cells, activated Treg cells expressed higher level of CD39 and predominantly produced inhibitory cytokines. In vitro assay showed that docetaxel reduced all three subsets of Treg cells. More importantly, we found docetaxel-based chemotherapy significantly decreased all three Treg subsets after 4 cycles of treatment in 17 NSCLC patients. Taken together, this study revealed dynamic changes of various Treg cell subsets in NSCLC patients before and after chemotherapy, providing activated Treg cells as a potential target for chemotherapy.

Show MeSH
Related in: MedlinePlus