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

Hypoxia-inducible factor 2 alpha (HIF-2 alpha) overexpression leads to activation of angiogenic pathways. However, little is known about the association between HIF-2 alpha expression and anti-tumor immunity in clear cell renal cell carcinoma (ccRCC). We aimed to explore how HIF-2 alpha influenced the microenvironment and the underlying mechanisms. We immunohistochemically evaluated immune cells infiltrations and prognostic value of HIF-2 alpha 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-2 alpha(high) tumors exhibited reduced overall survival (p = 0.025) and recurrence-free survival (p < 0.001). Functions of CD8(+) T cells were impaired in HIF-2 alpha(high) patients. In ccRCC patients, HIF-2 alpha 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-beta. HIF-2 alpha mRNA level adversely associated with immunostimulatory genes expression in KIRC and SATO cohorts. HIF-2 alpha contributed to evasion of anti-tumor immunity via SCF secretion and subsequent recruitment of mast cells in ccRCC patients.