B7-H1–expressing antigen-presenting cells mediate polarization of protumorigenic Th22 subsets
Dong-Ming Kuang, Xiao Xiao, Qiyi Zhao, Min-Min Chen, Xue-Feng Li, Rui-Xian Liu, Yuan Wei, Fang-Zhu Ouyang, Dong-Ping Chen, Yan Wu, Xiang-Ming Lao, Hong Deng, Limin Zheng
Dong-Ming Kuang, Xiao Xiao, Qiyi Zhao, Min-Min Chen, Xue-Feng Li, Rui-Xian Liu, Yuan Wei, Fang-Zhu Ouyang, Dong-Ping Chen, Yan Wu, Xiang-Ming Lao, Hong Deng, Limin Zheng
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Research Article Oncology

B7-H1–expressing antigen-presenting cells mediate polarization of protumorigenic Th22 subsets

Abstract

Classical IL-22–producing T helper cells (Th22 cells) mediate inflammatory responses independently of IFN-γ and IL-17; however, nonclassical Th22 cells have been recently identified and coexpress IFN-γ and/or IL-17 along with IL-22. Little is known about how classical and nonclassical Th22 subsets in human diseases are regulated. Here, we used samples of human blood, normal and peritumoral liver, and hepatocellular carcinoma (HCC) to delineate the phenotype, distribution, generation, and functional relevance of various Th22 subsets. Three nonclassical Th22 subsets constituted the majority of all Th22 cells in human liver and HCC tissues, although the classical Th22 subset was predominant in blood. Monocytes activated by TLR2 and TLR4 agonists served as the antigen-presenting cells (APCs) that most efficiently triggered the expansion of nonclassical Th22 subsets from memory T cells and classical Th22 subsets from naive T cells. Moreover, B7-H1–expressing monocytes skewed Th22 polarization away from IFN-γ and toward IL-17 through interaction with programmed death 1 (PD-1), an effect that can create favorable conditions for in vivo aggressive cancer growth and angiogenesis. Our results provide insight into the selective modulation of Th22 subsets and suggest that strategies to influence functional activities of inflammatory cells may benefit anticancer therapy.

Authors

Dong-Ming Kuang, Xiao Xiao, Qiyi Zhao, Min-Min Chen, Xue-Feng Li, Rui-Xian Liu, Yuan Wei, Fang-Zhu Ouyang, Dong-Ping Chen, Yan Wu, Xiang-Ming Lao, Hong Deng, Limin Zheng

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Figure 6

Protumorigenic roles of IL-22 and IL-17 in HCC.

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Protumorigenic roles of IL-22 and IL-17 in HCC. (A) Correlations between...
(A) Correlations between proportions of Th22 cells in tumor tissue from 26 patients and TNM or intrahepatic metastasis in patients. (B and C) Paraffin-embedded hepatoma samples were stained with an anti–IL-22 Ab. Scale bar: 50 μm. Based on the median value of IL-22+ cell density, patients were divided into low-density (n = 99) and high-density (n = 98) groups; cumulative OS and DFS times were calculated by the Kaplan-Meier method and analyzed by a log-rank test (C). (D and H) IL-22 plus IL-17 promoted the survival, proliferation, and proangiogenic activities of hepatoma cells. HepG2 cells undergoing serum starvation were stimulated with IL-22 alone or combined with IL-17 or IFN-γ (50 ng/ml for all) for 10 hours. Expression of the indicated proteins and genes (given as the mean) was determined by immunoblotting and real-time PCR, respectively. Results are representative of 4 separate experiments (n = 4–6). (E) Injection of T cells polarized by tumor monocytes significantly enhanced HepG2 hepatoma growth in mice; the effects were attenuated by additional injection of neutralizing Abs against IL-22 and IL-17. Data represent the mean ± SEM of 5 independent experiments (n = 6 for each). *P < 0.05, compared with the Medium group; #P < 0.05, compared with the T cell group (without B7-H1 mAb). (F and G) IL-22 plus IL-17 promoted the growth and angiogenesis of hepatoma in mice. Data represent the mean ± SEM (n = 5 for each group). *P < 0.05. Paraffin-embedded hepatoma samples were stained with an anti-CD34 Ab (G). Scale bar: 100 μm.