Tumor infiltrating mast cells determine oncogenic HIF-2α-conferred immune evasion in clear cell renal cell carcinoma
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.
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.
KeywordsClear cell renal cell carcinoma Hypoxia-inducible factor 2α Immune evasion Tumor infiltrating mast cells Stem cell factor
Clear cell renal cell carcinoma
Gene set enrichment analyses
Kidney clear cell carcinoma
Von Hippel-Lindau (VHL) protein
Renal cell carcinoma
Stem cell factor
The Cancer Genome Atlas
Tumor infiltrating mast cell
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 to use clinical samples and information was obtained from each patient.
- 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. https://doi.org/10.1074/jbc.M901790200 Google Scholar
- 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. https://doi.org/10.1016/j.ejca.2014.01.031 Google Scholar
- 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. https://doi.org/10.1093/carcin/bgs222 Google Scholar
- 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 79:958–963Google Scholar