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.
Graphic abstract
Similar content being viewed by others
References
Bray F, Ferlay J, Soerjomataram I et al (2018) Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 68(6):394–424
Schodel J, Grampp S, Maher ER et al (2016) Hypoxia, hypoxia-inducible transcription factors, and renal cancer. Eur Urol 69(4):646–657
Cohen HT, Mcgovern FJ (2005) Renal-cell carcinoma. N Engl J Med 353:2477–2490
Scherr AJ, Lima JPS, Sasse EC, Lima CS, Sasse AD (2011) Adjuvant therapy for locally advanced renal cell cancer: a systematic review with meta-analysis. BMC Cancer 11(1):115
Gupta K, Miller JD, Li JZ et al (2008) Epidemiologic and socioeconomic burden of metastatic renal cell carcinoma (mRCC): a literature review. Cancer Treat Rev 34(3):193–205
Rj M, Te Hutson PT (2007) Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med 356:115–124
Rini BI, Atkins MB (2009) Resistance to targeted therapy in renal-cell carcinoma. Lancet Oncol 10(10):992–1000
Motzer RJ, Tannir NM, Mcdermott DF et al (2018) Nivolumab plus ipilimumab versus sunitinib in advanced renal-cell carcinoma. N Engl J Med 378(14):1277–1290
Sade-Feldman M, Yizhak K, Bjorgaard SL et al (2018) Defining T cell states associated with response to checkpoint immunotherapy in melanoma. Cell 175(4):998–1013
Nakano Osamu, Sato Makoto, Naito Yoshitaka et al (2001) Proliferative activity of intratumoral CD8+ T-lymphocytes as a prognostic factor in human renal cell carcinoma. Cancer Res 61(13):5132–5136
Yao J, ** W, Zhu Y et al (2018) Checkpoint molecule PD-1-assisted CD8(+) T lymphocyte count in tumor microenvironment predicts overall survival of patients with metastatic renal cell carcinoma treated with tyrosine kinase inhibitors. Cancer Manag Res 10:3419–3431
Simoni Y, Becht E, Fehlings M et al (2018) Bystander CD8(+) T cells are abundant and phenotypically distinct in human tumour infiltrates. Nature 557(7706):575–579
Zhang H, Vijayan D, Li XY et al (2019) The role of NK cells and CD39 in the immunological control of tumor metastases. Oncoimmunology 8(6):e1593809
Bastid J, Regairaz A, Bonnefoy N et al (2015) Inhibition of CD39 enzymatic function at the surface of tumor cells alleviates their immunosuppressive activity. Cancer Immunol Res 3(3):254–265
Delahunt B, Srigley JR, Montironi R, Egevad L (2014) Advances in renal neoplasia: recommendations from the 2012 international society of urological pathology consensus conference. Urology 83(5):969–974
Edge SB, Compton CC (2010) The American Joint Committee on Cancer: the 7th edition of the AJCC cancer staging manual and the future of TNM. Ann Surg Oncol 17(6):1471
Eisenhauer EA, Therasse P et al (2009) New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 45:228
Frank I, Blute ML, Cheville JC, Lohse CM, Weaver AL, Zincke H (2002) An outcome prediction model for patients with clear cell renal cell carcinoma treated with radical nephrectomy based on tumor stage, size, grade and necrosis: the SSIGN score. J Urol 168(6):2395–2400
Young MD, Mitchell TJ, Vieira Braga FA et al (2018) Single-cell transcriptomes from human kidneys reveal the cellular identity of renal tumors. Science 361(6402):594–599
Wang J, Liu L, Qu Y et al (2016) Prognostic value of SETD2 expression in patients with metastatic renal cell carcinoma treated with tyrosine kinase inhibitors. J Urol 196(5):1363–1370
Brummelman J, Mazza EMC, Alvisi G et al (2018) High-dimensional single cell analysis identifies stem-like cytotoxic CD8(+) T cells infiltrating human tumors. J Exp Med 215(10):2520–2535
Finn OJ (2003) Cancer vaccines: between the idea and the reality. Nat Rev Immunol 3(8):630–641
Kishore BK, Robson SC, Dwyer KM (2018) CD39-adenosinergic axis in renal pathophysiology and therapeutics. Purinergic Signal 14(2):109–120
Li J, Wang L, Chen X et al (2017) CD39/CD73 upregulation on myeloid-derived suppressor cells via TGF-beta-mTOR-HIF-1 signaling in patients with non-small cell lung cancer. Oncoimmunology 6(6):e1320011
Matsumoto H, Thike AA, Li H et al (2016) Increased CD4 and CD8-positive T cell infiltrate signifies good prognosis in a subset of triple-negative breast cancer. Breast Cancer Res Treat 156(2):237–247
Mori M, Ohtani H, Naito Y et al (2000) Infiltration of CD8+ T cells in non-small cell lung cancer is associated with dedifferentiation of cancer cells, but not with prognosis. Tohoku J Exp Med 191:113–118
Galon J, Costes A, Sanchez-Cabo F et al (2006) Type, density, and location of immune cells within human colorectal tumors predict clinical outcome. Science 313(5795):1960–1964
Gourdin N, Bossennec M, Rodriguez C et al (2018) Autocrine adenosine regulates tumor polyfunctional CD73(+)CD4(+) effector T cells devoid of immune checkpoints. Cancer Res 78(13):3604–3618
Weijts BG, Bakker WJ, Cornelissen PW et al (2012) E2F7 and E2F8 promote angiogenesis through transcriptional activation of VEGFA in cooperation with HIF1. EMBO J 31(19):3871–3884
Beldi G, Wu Y, Sun X et al (2008) Regulated catalysis of extracellular nucleotides by vascular CD39/ENTPD1 is required for liver regeneration. Gastroenterology 135(5):1751–1760
Vigano S, Alatzoglou D, Irving M et al (2019) Targeting adenosine in cancer immunotherapy to enhance T-cell function. Front Immunol 10:925
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.
Author information
Authors and Affiliations
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
Ethics declarations
Conflict of interest
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.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Electronic supplementary material
Below is the link to the electronic supplementary material.
Rights and permissions
About this article
Cite this article
Qi, Y., **a, 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
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00262-020-02563-2