TGF-β1 contributes to CD8+ Treg induction through p38 MAPK signaling in ovarian cancer microenvironment.
CD8+ regulatory T cells (Tregs) contribute to cancer progression and immune evasion. We previously reported that CD8+ Tregs could be induced in vitro by co-culture of CD8+ T cells with the OC cell lines SKOV3/A2780. Here, we described the role of TGF-β1 in CD8+ Treg induction by the OC microenvironment. OC patients expressed high levels of TGF-β1, as did the co-culture supernatant from CD8+ T cells and SKOV3. Additionally, TGF-β1 levels were positively correlated with CD8+ Treg percentages in OC. Neutralization experiments, cytokine studies and proliferation assays revealed that the in vitro-induced CD8+Tregs depended at least partially on up-regulated expression of TGF-β1 to exert their suppressive function. CD8+ T cells cultured with SKOV3 exhibited marked activation of p38 MAPK than CD8+ T cells cultured alone, which could be inhibited by TGF-β1-neutralizing antibody. Moreover, the p38 specific inhibitor SB203580 dose-dependently blocked the TGF-β1 activated conversion of CD8+ T cells into CD8+ Tregs. These data suggested that in vitro-induction of CD8+ Tregs depended in part on TGF-β1 activation of p38 MAPK signaling. Therefore, p38 MAPK could be a therapeutic target in OC anti-tumor immunotherapy.
Department of Laboratory Medicine, The First Affiliated Hospital of Nanjing Medical University, 210029, Nanjing, China.|National Key Clinical Department of Laboratory Medicine, 210029, Nanjing, China.
Meng
M
Wu
Department of Laboratory Medicine, The First Affiliated Hospital of Nanjing Medical University, 210029, Nanjing, China.|National Key Clinical Department of Laboratory Medicine, 210029, Nanjing, China.
Xian
X
Chen
Department of Laboratory Medicine, The First Affiliated Hospital of Nanjing Medical University, 210029, Nanjing, China.|National Key Clinical Department of Laboratory Medicine, 210029, Nanjing, China.
Jianfang
J
Lou
Department of Laboratory Medicine, The Affiliated Children Hospital, Nanjing Medical University, 210029, Nanjing, China.
Shuping
S
Zhang
Department of Laboratory Medicine, The First Affiliated Hospital of Nanjing Medical University, 210029, Nanjing, China.|National Key Clinical Department of Laboratory Medicine, 210029, Nanjing, China.
Xiaojie
X
Zhang
Department of Laboratory Medicine, The First Affiliated Hospital of Nanjing Medical University, 210029, Nanjing, China.|National Key Clinical Department of Laboratory Medicine, 210029, Nanjing, China.
Lei
L
Huang
Department of Laboratory Medicine, The First Affiliated Hospital of Nanjing Medical University, 210029, Nanjing, China.|National Key Clinical Department of Laboratory Medicine, 210029, Nanjing, China.
Ruihong
R
Sun
Department of Laboratory Medicine, The First Affiliated Hospital of Nanjing Medical University, 210029, Nanjing, China.|National Key Clinical Department of Laboratory Medicine, 210029, Nanjing, China.
Peijun
P
Huang
Department of Laboratory Medicine, The First Affiliated Hospital of Nanjing Medical University, 210029, Nanjing, China.|National Key Clinical Department of Laboratory Medicine, 210029, Nanjing, China.
Fang
F
Wang
Department of Laboratory Medicine, The First Affiliated Hospital of Nanjing Medical University, 210029, Nanjing, China.|National Key Clinical Department of Laboratory Medicine, 210029, Nanjing, China.
Shiyang
S
Pan
D000328:Adult; D000368:Aged; D016827:CD8 Antigens / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D018920:Coculture Techniques; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008875:Middle Aged; D010051:Ovarian Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D011725:Pyridines / Q000494:pharmacology; D050378:T-Lymphocytes, Regulatory / Q000378:metabolism*; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism*; D059016:Tumor Microenvironment / Q000187:drug effects; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*
D016827:CD8 Antigens; D004791:Enzyme Inhibitors; D007093:Imidazoles; D011725:Pyridines; D053773:Transforming Growth Factor beta1; D048051:p38 Mitogen-Activated Protein Kinases; C093642:SB 203580
CD8+ Treg; TGF-β1; ovarian cancer; p38 MAPK