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

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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.

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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

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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.

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Author notes

  1. Ying **ong, Li Liu and Yu **a contributed equally to this work.

Authors and Affiliations

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

    Ying **ong, Li Liu, Yu **a, Yang Qu, Zewei Wang, Zhiyuan Lin, **ang Chen, Zhuoyi **ang, Jiajun Wang, Qi Bai, Yuanfeng Yang & Jianming Guo

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

    Yangyang Qi, Yifan Chen & Weijuan Zhang

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

    Lingli Chen

  4. Department of Pathology, Rui** Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China

    Peipei Zhang

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

    Yunyi Kong

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

    Jiejie Xu

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  1. Ying **ong
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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.

Corresponding authors

Correspondence to Jianming Guo or Jiejie Xu.

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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.

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

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**ong, Y., Liu, L., **a, Y. et al. Tumor infiltrating mast cells determine oncogenic HIF-2α-conferred immune evasion in clear cell renal cell carcinoma. Cancer Immunol Immunother 68, 731–741 (2019). https://doi.org/10.1007/s00262-019-02314-y

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