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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

Abstract

Purpose

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.

Results

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.

Conclusions

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

Keywords

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

Abbreviations

ccRCC

Clear cell renal cell carcinoma

GAPDH

Glyceraldehyde-3-phosphate dehydrogenase

GO

Gene ontology

GSEA

Gene set enrichment analyses

HIF

Hypoxia-inducible factors

KIRC

Kidney clear cell carcinoma

pVHL

Von Hippel-Lindau (VHL) protein

RCC

Renal cell carcinoma

SCF

Stem cell factor

TCGA

The Cancer Genome Atlas

TIM

Tumor infiltrating mast cell

VHL

Von Hippel-Lindau

Notes

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.

Funding

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)

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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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