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Tumor-infiltrating CD39+CD8+ T cells determine poor prognosis and immune evasion in clear cell renal cell carcinoma patients

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Abstract

Purpose

Tumor microenvironment is important in the progression of clear cell renal cell carcinoma (ccRCC), and its prognostic value is still unclear. Recent reports demonstrated tumor-infiltrating CD39+CD8+ T cells are abundant, but their function remains obscure. We aim to assess clinical value of CD39+CD8+ T cells and seek a potential therapeutic target in ccRCC.

Experimental design

We immunohistochemically evaluated clinical value of CD39+CD8+ T cells in a retrospective Zhongshan Hospital cohort of 243 ccRCC patients. Fresh tumor samples (n = 48), non-tumor tissues and peripheral blood for flow cytometry analyses were collected to analyze immune cell functions from Zhongshan Hospital. The survival benefit of tyrosine kinase inhibitors (TKIs) in this subpopulation was evaluated. Kaplan–Meier analysis and COX regression model were applied for survival analyses. Bioinformatics analysis performed in TCGA KIRC cohort and the scRNA-seq cohort.

Results

We found that accumulation of CD39+CD8+ T cells indicated poor prognosis (p < 0.0001) and indicated therapeutic benefit of TKIs therapy (p = 0.015). CD39+CD8+ T cells showed decreased TNF-α and IFN-γ with elevated PD-1 and TIM-3 expression. Further analysis of tumor-infiltrating immune cell landscape in the ccRCC revealed the positive correlation between CD39+CD8+ T cells and Tregs (p = 0.037) and M2-polarized macrophages (p < 0.0001). Finally, inhibition of CD39 partially restores the anti-tumor function of CD8+ T cells.

Conclusions

High CD39+CD8+ T cells indicated poor prognosis in ccRCC, due to impaired anti-tumor function of CD39+CD8+ T cells and indicated therapeutic benefit of TKIs therapy.

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Acknowledgements

We thank the financial support from grants from National Natural Science Foundation of China (81671628, 31770851, 81702496, 81702497, 81702805, 81772696, 81871306, 81872082, 81902556, 81902563, 81902898, 81974393), National Key R&D Program of China (2017YFC0114303), Shanghai Municipal Natural Science Foundation (16ZR1406500, 17ZR1405100, 19ZR1431800), Guide Project of Science and Technology Commission of Shanghai Municipality (17411963100), Shanghai Sailing Program (18YF1404500, 19YF1407900, 19YF1427200), Shanghai Municipal Commission of Health and Family Planning Program (20174Y0042, 201840168, 20184Y0151), Fudan University Shanghai Cancer Center for Outstanding Youth Scholars Foundation (YJYQ201802) and Shanghai Cancer Research Charity Center. All these study sponsors have no roles in the study design, collection, analysis and interpretation of data.

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Author notes

  1. Yu Qi, Yu Xia, Zhiyuan Lin, and Yang Qu authors have contributed equally to this work.

Authors and Affiliations

  1. Department of Urology, Zhongshan Hospital, Fudan University, Shanghai, 200032, China

    Yu Qi, Yu Xia, Zhiyuan Lin, Yang Qu, Jiajun Wang, Qi Bai, Li Liu & Jianming Guo

  2. Department of Immunology, School of Basic Medical Sciences, Fudan University, Shanghai, China

    Yangyang Qi, Yifan Chen & Weijuan Zhang

  3. Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, 200032, China

    Quan Zhou, Han Zeng & Jiejie Xu

  4. Department of Urology, Fudan University Shanghai Cancer Center, Shanghai, China

    Yuan Chang, Yu Zhu & Bo Dai

  5. Department of Urology, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China

    Yiwei Wang

  6. Department of Urology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China

    Le Xu

  7. Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai, China

    Lingli Chen

  8. Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, China

    Yunyi Kong

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  1. Yu Qi
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  2. Yu Xia
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  19. Li Liu
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Contributions

YQ, YX, ZL and YQ were involved in acquisition of data, analysis and interpretation of data, statistical analysis and drafting of the manuscript; YQ, YC, QZ, HZ, JW, YC, QB, YW, YZ, LX, LC, YK, WZ and BD contributed to technical and material support; LL, JG and JX were involved in study concept and design, analysis and interpretation of data, drafting of the manuscript, funding and study supervision. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Li Liu, Jianming Guo or Jiejie Xu.

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The authors declare no conflict of interest.

Ethical standard

This study was approved by the Clinical Research Ethics Committee of Zhongshan Hospital, Fudan University, with the approval number B2015-030. Informed consent was obtained from each patient included in this study. Our study followed the Helsinki declaration.

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Qi, Y., Xia, Y., Lin, Z. et al. Tumor-infiltrating CD39+CD8+ T cells determine poor prognosis and immune evasion in clear cell renal cell carcinoma patients. Cancer Immunol Immunother 69, 1565–1576 (2020). https://doi.org/10.1007/s00262-020-02563-2

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