肿瘤浸润肥大细胞决定透明细胞肾细胞癌中致癌 HIF-2α 介导的免疫逃逸。
Tumor infiltrating mast cells determine oncogenic HIF-2α-conferred immune evasion in clear cell renal cell carcinoma.
机构信息
Department of Urology, Zhongshan Hospital, Fudan University, Shanghai, China.
Department of Immunology, School of Basic Medical Sciences, Fudan University, Shanghai, China.
出版信息
Cancer Immunol Immunother. 2019 May;68(5):731-741. doi: 10.1007/s00262-019-02314-y. Epub 2019 Feb 13.
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-2α tumors exhibited reduced overall survival (p = 0.025) and recurrence-free survival (p < 0.001). Functions of CD8 T cells were impaired in HIF-2α 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.
目的
缺氧诱导因子 2α（HIF-2α）过表达可导致血管生成途径的激活。然而，对于 HIF-2α 在透明细胞肾细胞癌（ccRCC）中的表达与抗肿瘤免疫之间的关系知之甚少。我们旨在探讨 HIF-2α 如何影响肿瘤微环境及其潜在机制。
实验设计
我们通过回顾性中山大学附属中山医院 280 例 ccRCC 患者的免疫组织化学评估，研究了 HIF-2α 表达与免疫细胞浸润的相关性及其预后价值。我们收集了 2017 年 9 月至 2018 年 4 月在中山大学附属中山医院接受肾切除术的患者的新鲜肿瘤样本、非肿瘤组织和自体外周血，用于 RT-PCR、ELISA 和流式细胞术分析。我们评估了 TCGA KIRC 队列和 SATO 队列来支持我们的研究结果。
结果
我们发现，HIF-2α 阳性的 ccRCC 患者总生存（p=0.025）和无复发生存（p<0.001）降低。HIF-2α 患者的 CD8 T 细胞功能受损。在 ccRCC 患者中，HIF-2α 诱导了干细胞因子（SCF）的表达，SCF 作为肥大细胞的趋化因子。肿瘤浸润肥大细胞通过分泌 IL-10 和 TGF-β 部分损害抗肿瘤免疫。在 KIRC 和 SATO 队列中，HIF-2α mRNA 水平与免疫刺激基因的表达呈负相关。
结论
HIF-2α 通过分泌 SCF 并随后招募 ccRCC 患者中的肥大细胞，促进了抗肿瘤免疫的逃逸。
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