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Elimination of CD4lowHLA-G+ T cells overcomes castration-resistance in prostate cancer therapy

Cell Research (2018) | Download Citation

Abstract

Androgen deprivation therapy (ADT) is a main treatment for prostate cancer (PCa) but the disease often recurs and becomes castration-resistant in nearly all patients. Recent data implicate the involvement of immune cells in the development of this castration-resistant prostate cancer (CRPC). In particular, T cells have been found to be expanded in both PCa patients and mouse models shortly after androgen deprivation. However, whether or which of the T cell subtypes play an important role during the development of CRPC is unknown. Here we identified a novel population of CD4lowHLA-G+ T cells that undergo significant expansion in PCa patients after ADT. In mouse PCa models, a similar CD4low T cell population expands during the early stages of CRPC onset. These cells are identified as IL-4-expressing TH17 cells, and are shown to be associated with CRPC onset in patients and essential for the development of CRPC in mouse models. Mechanistically, CD4lowHLA-G+ T cells drive androgen-independent growth of prostate cancer cells by modulating the activity and migration of CD11blowF4/80hi macrophages. Furthermore, following androgen deprivation, elevated PGE2-EP2 signaling inhibited the expression of CD4 in thymocytes, and subsequently induced the polarization of CD4low naïve T cells towards the IL-4-expressing TH17 phenotype via up-regulation of IL23R. Therapeutically, inactivating PGE2 signaling with celecoxib at a time when CD4lowHLA-G+ T cells appeared, but not immediately following androgen deprivation, dramatically suppressed the onset of CRPC. Collectively, our results indicate that an unusual population of CD4lowHLA-G+ T cells is essential for the development of CRPC and point to a new therapeutic avenue of combining ADT with PGE2 inhibition for the treatment of prostate cancer.

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Acknowledgements

We thank M.H.Y. for his suggestions and editing. The study is supported by funds to Y.Z. from the National Natural Science Foundation of China (NSFC, 81372257 and 81773250), to W.Q.G. from the Chinese Ministry of Science and Technology (2017YFA0102900), NSFC 81630073 and 81872406, Science and Technology Commission of Shanghai Municipality (16JC1405700) and KC Wong foundation, and to W.L. from NSFC 81400458.

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Affiliations

  1. State Key Laboratory of Oncogenes and Related Genes, Renji-MedX stem Cell Research Center, Ren Ji Hospital, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, 200030, China

    • Chao Wang
    • , Qianfei Zhang
    • , Wang Li
    • , Shengbo Zhang
    • , Yanjie Xu
    • , Fang Wang
    • , Yan Zhang
    •  & Wei-Qiang Gao
  2. Med-X Research Institute & School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, 200030, China

    • Chao Wang
    • , Qianfei Zhang
    • , Shengbo Zhang
    • , Yanjie Xu
    • , Yan Zhang
    •  & Wei-Qiang Gao
  3. Key Laboratory of Systems Biomedicine, Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, Shanghai, 200240, China

    • Jiahuan Chen
    •  & Bing Zhang

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Contributions

W.Q.G., Y.Z. and C.W. conceived the project, performed experiments, analyzed data, and wrote the manuscript. Q.F.Z. performed experiments and analyzed data. B.Z. and J.H.C. analyzed RNA-seq data. S.B.Z. and Y.J.X. performed immunohistochemical analysis. W.L. and F.W. assisted with flow cytometry. All authors discussed the results and commented on the manuscript.

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The authors declare no competing interests.

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Correspondence to Yan Zhang or Wei-Qiang Gao.

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https://doi.org/10.1038/s41422-018-0089-4