Cancer Immunology, Immunotherapy

, Volume 68, Issue 5, pp 731–741 | Cite as

Tumor infiltrating mast cells determine oncogenic HIF-2α-conferred immune evasion in clear cell renal cell carcinoma

  • Ying Xiong
  • Li Liu
  • Yu Xia
  • Yangyang Qi
  • Yifan Chen
  • Lingli Chen
  • Peipei Zhang
  • Yunyi Kong
  • Yang Qu
  • Zewei Wang
  • Zhiyuan Lin
  • Xiang Chen
  • Zhuoyi Xiang
  • Jiajun Wang
  • Qi Bai
  • Weijuan Zhang
  • Yuanfeng Yang
  • Jianming GuoEmail author
  • Jiejie XuEmail author
Original Article



Hypoxia-inducible factor 2α (HIF-2α) overexpression leads to activation of angiogenic pathways. However, little is known about the association between HIF-2α expression and anti-tumor immunity in clear cell renal cell carcinoma (ccRCC). We aimed to explore how HIF-2α influenced the microenvironment and the underlying mechanisms.

Experimental design

We immunohistochemically evaluated immune cells infiltrations and prognostic value of HIF-2α expression in a retrospective Zhongshan Hospital cohort of 280 ccRCC patients. Fresh tumor samples, non-tumor tissues and autologous peripheral blood for RT-PCR, ELISA and flow cytometry analyses were collected from patients who underwent nephrectomy in Zhongshan Hospital from September 2017 to April 2018. The TCGA KIRC cohort and SATO cohort were assessed to support our findings.


We demonstrated that ccRCC patients with HIF-2αhigh tumors exhibited reduced overall survival (p = 0.025) and recurrence-free survival (p < 0.001). Functions of CD8+ T cells were impaired in HIF-2αhigh patients. In ccRCC patients, HIF-2α induced the expression of stem cell factor (SCF), which served as chemoattractant for mast cells. Tumor infiltrating mast cells impaired anti-tumor immunity partly by secreting IL-10 and TGF-β. HIF-2α mRNA level adversely associated with immunostimulatory genes expression in KIRC and SATO cohorts.


HIF-2α contributed to evasion of anti-tumor immunity via SCF secretion and subsequent recruitment of mast cells in ccRCC patients.


Clear cell renal cell carcinoma Hypoxia-inducible factor 2α Immune evasion Tumor infiltrating mast cells Stem cell factor 



Clear cell renal cell carcinoma


Glyceraldehyde-3-phosphate dehydrogenase


Gene ontology


Gene set enrichment analyses


Hypoxia-inducible factors


Kidney clear cell carcinoma


Von Hippel-Lindau (VHL) protein


Renal cell carcinoma


Stem cell factor


The Cancer Genome Atlas


Tumor infiltrating mast cell


Von Hippel-Lindau


Author contributions

Acquisition of data, analysis and interpretation of data, statistical analysis and drafting of the manuscript were carried out by YX, LL and YX; YQ, YC, LC, PZ, YK, YQ, ZW, ZL, XC, ZX, JW, QB, WZ and YY provided technical and material support; JG and JX were responsible for the study concept and design, analysis and interpretation of data, drafting of the manuscript, obtained funding and study supervision. All authors read and approved the final manuscript.


This work was supported by grants from National Natural Science Foundation of China (81471621, 81472227, 81472376, 81671628, 31770851, 81702496, 81702497, 81702805, 81772696, 81871306), Shanghai Municipal Natural Science Foundation (17ZR1405100), Shanghai Municipal Commission of Health and Family Planning (20174Y0042), and Zhongshan Hospital Science Foundation (2016ZSQN30, 2017ZSQN18, 2017ZSYQ26). All these study sponsors have no roles in design of the study or collection, analysis, and interpretation of data.

Compliance with ethical standards

Conflict of interest

The authors declare no conflict of interest.

Ethical approval and ethical standards

The study was approved by the Clinical Research Ethics Committee of Zhongshan Hospital, Fudan University with the approval number B2015-030. Our study followed the Helsinki declaration.

Informed consent

Informed consent to use clinical samples and information was obtained from each patient.

Supplementary material

262_2019_2314_MOESM1_ESM.pdf (1.7 mb)
Supplementary material 1 (PDF 1723 KB)


  1. 1.
    Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A (2015) Global cancer statistics, 2012. CA Cancer J Clin 65:87–108. CrossRefGoogle Scholar
  2. 2.
    Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM (2010) Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer 127:2893–2917. CrossRefGoogle Scholar
  3. 3.
    Cohen HT, McGovern FJ (2005) Renal-cell carcinoma. N Engl J Med 353:2477–2490. CrossRefPubMedGoogle Scholar
  4. 4.
    Gupta K, Miller JD, Li JZ, Russell MW, Charbonneau C (2008) Epidemiologic and socioeconomic burden of metastatic renal cell carcinoma (mRCC): a literature review. Cancer Treat Rev 34:193–205. CrossRefPubMedGoogle Scholar
  5. 5.
    Escudier B (2012) Emerging immunotherapies for renal cell carcinoma. Ann Oncol 23(Suppl 8):viii35–40. CrossRefPubMedGoogle Scholar
  6. 6.
    Atkins MB, Regan M, McDermott D (2004) Update on the role of interleukin 2 and other cytokines in the treatment of patients with stage IV renal carcinoma. Clin Cancer Res 10:6342S–6342S6S. CrossRefPubMedGoogle Scholar
  7. 7.
    Nyhan MJ, O’Sullivan GC, McKenna SL (2008) Role of the VHL (von Hippel-Lindau) gene in renal cancer: a multifunctional tumour suppressor. Biochem Soc Trans 36:472–478. CrossRefPubMedGoogle Scholar
  8. 8.
    Farber LJ, Furge K, Teh BT (2012) Renal cell carcinoma deep sequencing: recent developments. Curr Oncol Rep 14:240–248. CrossRefPubMedGoogle Scholar
  9. 9.
    Schodel J, Grampp S, Maher ER, Moch H, Ratcliffe PJ, Russo P, Mole DR (2016) Hypoxia, Hypoxia-inducible Transcription Factors, and Renal Cancer. Eur Urol 69:646–657. CrossRefPubMedGoogle Scholar
  10. 10.
    Schodel J, Oikonomopoulos S, Ragoussis J, Pugh CW, Ratcliffe PJ, Mole DR (2011) High-resolution genome-wide mapping of HIF-binding sites by ChIP-sEq. Blood 117:e207–e217. CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Mole DR, Blancher C, Copley RR, Pollard PJ, Gleadle JM, Ragoussis J, Ratcliffe PJ (2009) Genome-wide association of hypoxia-inducible factor (HIF)-1alpha and HIF-2alpha DNA binding with expression profiling of hypoxia-inducible transcripts. J Biol Chem 284:16767–16775. CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Raval RR, Lau KW, Tran MG et al (2005) Contrasting properties of hypoxia-inducible factor 1 (HIF-1) and HIF-2 in von Hippel-Lindau-associated renal cell carcinoma. Mol Cell Biol 25:5675–5686. CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Kroeger N, Seligson DB, Signoretti S, Yu H, Magyar CE, Huang J, Belldegrun AS, Pantuck AJ (2014) Poor prognosis and advanced clinicopathological features of clear cell renal cell carcinoma (ccRCC) are associated with cytoplasmic subcellular localisation of Hypoxia inducible factor-2alpha. Eur J Cancer 50:1531–1540. CrossRefPubMedGoogle Scholar
  14. 14.
    Biswas S, Charlesworth PJ, Turner GD et al (2012) CD31 angiogenesis and combined expression of HIF-1alpha and HIF-2alpha are prognostic in primary clear-cell renal cell carcinoma (CC-RCC), but HIFalpha transcriptional products are not: implications for antiangiogenic trials and HIFalpha biomarker studies in primary CC-RCC. Carcinogenesis 33:1717–1725. CrossRefPubMedGoogle Scholar
  15. 15.
    Wallace EM, Rizzi JP, Han G et al (2016) A small-molecule antagonist of HIF2alpha is efficacious in preclinical models of renal cell carcinoma. Cancer Res 76:5491–5500. CrossRefPubMedGoogle Scholar
  16. 16.
    Cho H, Kaelin WG (2016) Targeting HIF2 in clear cell renal cell carcinoma. Cold Spring Harb Symp Quant Biol 81:113–121. CrossRefPubMedGoogle Scholar
  17. 17.
    Palucka AK, Coussens LM (2016) The basis of oncoimmunology. Cell 164:1233–1247. CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Chen DS, Mellman I (2013) Oncology meets immunology: the cancer-immunity cycle. Immunity 39:1–10. CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Vandyke K, Zeissig MN, Hewett DR et al (2017) HIF-2alpha promotes dissemination of plasma cells in multiple myeloma by regulating CXCL12/CXCR4 and CCR1. Cancer Res 77:5452–5463. CrossRefPubMedGoogle Scholar
  20. 20.
    Yamamura K, Uruno T, Shiraishi A et al (2017) The transcription factor EPAS1 links DOCK8 deficiency to atopic skin inflammation via IL-31 induction. Nat Commun 8:13946. CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Messai Y, Noman MZ, Hasmim M, Escudier B, Chouaib S (2015) HIF-2alpha/ITPR1 axis: a new saboteur of NK-mediated lysis. Oncoimmunology 4:e985951. CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Sato Y, Yoshizato T, Shiraishi Y et al (2013) Integrated molecular analysis of clear-cell renal cell carcinoma. Nat Genet 45:860–867. CrossRefGoogle Scholar
  23. 23.
    Gentles AJ, Newman AM, Liu CL et al (2015) The prognostic landscape of genes and infiltrating immune cells across human cancers. Nat Med 21:938–945. CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Szklarczyk D, Franceschini A, Wyder S et al (2015) STRING v10: protein-protein interaction networks, integrated over the tree of life. Nucleic Acids Res 43:D447–D452. CrossRefGoogle Scholar
  25. 25.
    Shannon P, Markiel A, Ozier O, Baliga NS, Wang JT, Ramage D, Amin N, Schwikowski B, Ideker T (2003) Cytoscape: a software environment for integrated models of biomolecular interaction networks. Genome Res 13:2498–2504. CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Benito-Martin A, Peinado H (2015) FunRich proteomics software analysis, let the fun begin! Proteomics. 15:2555–2556. CrossRefPubMedGoogle Scholar
  27. 27.
    Subramanian A, Tamayo P, Mootha VK et al (2005) Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci USA 102:15545–15550. CrossRefGoogle Scholar
  28. 28.
    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 196:1363–1370. CrossRefPubMedGoogle Scholar
  29. 29.
    Liu H, Xu J, Zhou L, Yun X, Chen L, Wang S, Sun L, Wen Y, Gu J (2011) Hepatitis B virus large surface antigen promotes liver carcinogenesis by activating the Src/PI3K/Akt pathway. Cancer Res 71:7547–7557. CrossRefPubMedGoogle Scholar
  30. 30.
    Wang X, Dong J, Jia L et al (2017) HIF-2-dependent expression of stem cell factor promotes metastasis in hepatocellular carcinoma. Cancer Lett 393:113–124. CrossRefPubMedGoogle Scholar
  31. 31.
    Meininger CJ, Yano H, Rottapel R, Bernstein A, Zsebo KM, Zetter BR (1992) The c-kit receptor ligand functions as a mast cell chemoattractant. Blood 79:958–963PubMedGoogle Scholar
  32. 32.
    Hanahan D, Weinberg RA (2011) Hallmarks of cancer: the next generation. Cell 144:646–674. CrossRefPubMedGoogle Scholar
  33. 33.
    Disis ML (2010) Immune regulation of cancer. J Clin Oncol 28:4531–4538. CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Baldewijns MM, van Vlodrop IJ, Vermeulen PB, Soetekouw PM, van Engeland M, de Bruine AP (2010) VHL and HIF signalling in renal cell carcinogenesis. J Pathol 221:125–138. CrossRefPubMedGoogle Scholar
  35. 35.
    Khazaie K, Blatner NR, Khan MW et al (2011) The significant role of mast cells in cancer. Cancer Metastasis Rev 30:45–60. CrossRefPubMedGoogle Scholar
  36. 36.
    Marech I, Gadaleta CD, Ranieri G (2014) Possible prognostic and therapeutic significance of c-Kit expression, mast cell count and microvessel density in renal cell carcinoma. Int J Mol Sci 15:13060–13076. CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Chen W, Hill H, Christie A et al (2016) Targeting renal cell carcinoma with a HIF-2 antagonist. Nature 539:112–117. CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Ribatti D (2016) Mast cells as therapeutic target in cancer. Eur J Pharmacol 778:152–157. CrossRefPubMedGoogle Scholar
  39. 39.
    Schreiber RD, Old LJ, Smyth MJ (2011) Cancer immunoediting: integrating immunity’s roles in cancer suppression and promotion. Science 331:1565–1570. CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Ying Xiong
    • 1
  • Li Liu
    • 1
  • Yu Xia
    • 1
  • Yangyang Qi
    • 2
  • Yifan Chen
    • 2
  • Lingli Chen
    • 3
  • Peipei Zhang
    • 4
  • Yunyi Kong
    • 5
  • Yang Qu
    • 1
  • Zewei Wang
    • 1
  • Zhiyuan Lin
    • 1
  • Xiang Chen
    • 1
  • Zhuoyi Xiang
    • 1
  • Jiajun Wang
    • 1
  • Qi Bai
    • 1
  • Weijuan Zhang
    • 2
  • Yuanfeng Yang
    • 1
  • Jianming Guo
    • 1
    Email author
  • Jiejie Xu
    • 6
    Email author
  1. 1.Department of Urology, Zhongshan HospitalFudan UniversityShanghaiChina
  2. 2.Department of Immunology, School of Basic Medical SciencesFudan UniversityShanghaiChina
  3. 3.Department of Pathology, Zhongshan HospitalFudan UniversityShanghaiChina
  4. 4.Department of PathologyRuijin Hospital, Shanghai Jiao Tong University School of MedicineShanghaiChina
  5. 5.Department of PathologyFudan University Shanghai Cancer CenterShanghaiChina
  6. 6.Department of Biochemistry and Molecular Biology, School of Basic Medical SciencesFudan UniversityShanghaiChina

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