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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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aTreg but not rTreg and non-Treg cells increased in NSCLC patients. (a) CD4+Foxp3+ T cells and three subsets of Treg cells from PBMCs were isolated and analyzed by FACS. (b) The percentages of Treg cells (CD4+Foxp3+ T (total Treg) cells, CD4+CD45RA−Foxp3hi (aTreg) cells, CD4+CD45RA−Foxp3lo (non-Treg) cells, and CD4+CD45RA+Foxp3lo (rTreg) cells) in CD4+ T cells were calculated after FACS analysis. HD: healthy donor, n = 20; NSCLC: nonsmall cell lung cancer, n = 40. Each dot represents one individual sample. **P < 0.01 and ***P < 0.001 for statistical analysis by Student's t-test.
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fig1: aTreg but not rTreg and non-Treg cells increased in NSCLC patients. (a) CD4+Foxp3+ T cells and three subsets of Treg cells from PBMCs were isolated and analyzed by FACS. (b) The percentages of Treg cells (CD4+Foxp3+ T (total Treg) cells, CD4+CD45RA−Foxp3hi (aTreg) cells, CD4+CD45RA−Foxp3lo (non-Treg) cells, and CD4+CD45RA+Foxp3lo (rTreg) cells) in CD4+ T cells were calculated after FACS analysis. HD: healthy donor, n = 20; NSCLC: nonsmall cell lung cancer, n = 40. Each dot represents one individual sample. **P < 0.01 and ***P < 0.001 for statistical analysis by Student's t-test.

Mentions: The combination of Foxp3 and CD45RA staining of CD4+ T cells in PBMCs of NSCLC patients revealed the existence of three subsets of Treg cells (Figure 1(a)). Notably, these three CD4+Foxp3+ populations could be distinctly separated into Foxp3loCD45RA+ cells (rTreg cells), Foxp3hiCD45RA− cells (aTreg cells), and Foxp3loCD45RA− cells (non-Treg cells). As shown in Figure 1(b), the percentage of CD4+Foxp3+ Treg cells from PBMCs increased in NSCLC patients compared to healthy donors (1.76 ± 0.17% versus 1.01 ± 0.16%, P < 0.01). We further analyzed three subsets of CD4+Foxp3+ cells in total CD4+ T cells. Our data showed that only aTreg cells but not rTreg or non-Treg cells increased in NSCLC patients compared to healthy donors (1.07 ± 0.16% versus 0.25 ± 0.04%, P < 0.001), indicating that aTreg cells might play an important role in the pathogenesis of lung cancer.


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)

aTreg but not rTreg and non-Treg cells increased in NSCLC patients. (a) CD4+Foxp3+ T cells and three subsets of Treg cells from PBMCs were isolated and analyzed by FACS. (b) The percentages of Treg cells (CD4+Foxp3+ T (total Treg) cells, CD4+CD45RA−Foxp3hi (aTreg) cells, CD4+CD45RA−Foxp3lo (non-Treg) cells, and CD4+CD45RA+Foxp3lo (rTreg) cells) in CD4+ T cells were calculated after FACS analysis. HD: healthy donor, n = 20; NSCLC: nonsmall cell lung cancer, n = 40. Each dot represents one individual sample. **P < 0.01 and ***P < 0.001 for statistical analysis by Student's t-test.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig1: aTreg but not rTreg and non-Treg cells increased in NSCLC patients. (a) CD4+Foxp3+ T cells and three subsets of Treg cells from PBMCs were isolated and analyzed by FACS. (b) The percentages of Treg cells (CD4+Foxp3+ T (total Treg) cells, CD4+CD45RA−Foxp3hi (aTreg) cells, CD4+CD45RA−Foxp3lo (non-Treg) cells, and CD4+CD45RA+Foxp3lo (rTreg) cells) in CD4+ T cells were calculated after FACS analysis. HD: healthy donor, n = 20; NSCLC: nonsmall cell lung cancer, n = 40. Each dot represents one individual sample. **P < 0.01 and ***P < 0.001 for statistical analysis by Student's t-test.
Mentions: The combination of Foxp3 and CD45RA staining of CD4+ T cells in PBMCs of NSCLC patients revealed the existence of three subsets of Treg cells (Figure 1(a)). Notably, these three CD4+Foxp3+ populations could be distinctly separated into Foxp3loCD45RA+ cells (rTreg cells), Foxp3hiCD45RA− cells (aTreg cells), and Foxp3loCD45RA− cells (non-Treg cells). As shown in Figure 1(b), the percentage of CD4+Foxp3+ Treg cells from PBMCs increased in NSCLC patients compared to healthy donors (1.76 ± 0.17% versus 1.01 ± 0.16%, P < 0.01). We further analyzed three subsets of CD4+Foxp3+ cells in total CD4+ T cells. Our data showed that only aTreg cells but not rTreg or non-Treg cells increased in NSCLC patients compared to healthy donors (1.07 ± 0.16% versus 0.25 ± 0.04%, P < 0.001), indicating that aTreg cells might play an important role in the pathogenesis of lung cancer.

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