Depletion of regulatory T cells facilitates growth of established tumors: a mechanism involving the regulation of myeloid-derived suppressor cells by lipoxin A4.
Regulatory T cells (Tregs) are thought to facilitate tumor development by suppressing protective antitumor immune responses. However, recent clinical and laboratory studies show that Tregs are a favorable element against cancer. In this study, we provide evidence that Tregs have both promoting and inhibiting effects on tumors, depending on the stage of tumor development. By using 0.5 mg cyclophosphamide, we constructed a murine liver cancer model in which Tregs were continuously and selectively depleted. Under such conditions, we found that tumor growth was inhibited at early stages but accelerated later on. Analysis of the tumor microenvironment disclosed that long-term Treg depletion by 0.5 mg cyclophosphamide treatment induced Gr-1(+)CD11b(+) myeloid-derived suppressor cells (MDSCs). Ablation of MDSCs by anti-Gr-1 Ab blocked Treg depletion-induced promotion of tumor growth. Furthermore, lipoxygenases 5 and 12, two enzymes participating in the biosynthesis of the lipid anti-inflammatory mediator lipoxin A(4), were upregulated or downregulated by Treg depletion or adoptive transfer. Correspondingly, the levels of lipoxin A(4) were increased or decreased. Lipoxin A(4) thus regulated the induction of MDSCs in response to Treg depletion. These findings suggest that Tregs may play different roles at different stages of tumor growth: promoting early and inhibiting late tumor growth. Our study also suggests that the interplay among Tregs, MDSCs, and lipoxin A(4) tunes the regulation of tumor-associated inflammation.
Department of Biochemistry and Molecular Biology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, People's Republic of China.
Biao
B
Zhang
Haibo
H
Jia
Jing
J
Liu
Zhuoshun
Z
Yang
Tao
T
Jiang
Ke
K
Tang
Dapeng
D
Li
Chunmei
C
Huang
Jingwei
J
Ma
Guan-Xin
GX
Shen
Duyun
D
Ye
Bo
B
Huang
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology; D003520:Cyclophosphamide / Q000009:adverse effects / Q000494:pharmacology; D007249:Inflammation / Q000139:chemically induced / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D044045:Lipoxins / Q000096:biosynthesis / Q000276:immunology*; D058945:Lipoxygenases / Q000096:biosynthesis / Q000276:immunology; D008113:Liver Neoplasms / Q000139:chemically induced / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D008212:Lymphocyte Depletion; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009153:Mutagens / Q000009:adverse effects / Q000494:pharmacology; D022423:Myeloid Cells / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D009374:Neoplasms, Experimental / Q000139:chemically induced / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D011956:Receptors, Cell Surface / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism / Q000473:pathology
D000911:Antibodies, Monoclonal; D044045:Lipoxins; D009153:Mutagens; D011956:Receptors, Cell Surface; C551746:granulocyte receptor 1, mouse; C040527:lipoxin A4; D003520:Cyclophosphamide; D058945:Lipoxygenases