缺氧(环境)
肺癌
间歇性缺氧
下调和上调
免疫系统
癌症研究
肿瘤缺氧
医学
肿瘤进展
PD-L1
肺
腺癌
癌症
免疫学
内科学
免疫疗法
生物
阻塞性睡眠呼吸暂停
化学
生物化学
有机化学
氧气
基因
放射治疗
作者
Zhilei Cui,Zhengshang Ruan,Meigui Li,Rongrong Ren,Yizong Ma,Junxiang Zeng,Jinyuan Sun,Wenjing Ye,Weiguo Xu,Xuejun Guo,Dengfei Xu,Linlin Zhang
标识
DOI:10.1016/j.intimp.2023.110652
摘要
Accumulating evidence has shown an increased tumor incidence and reduced survival rate in cancer patients with obstructive sleep apnea (OSA). Although intermittent hypoxia is known to play a crucial role, the molecular mechanism by which intermittent hypoxia accelerates lung cancer progression remains to be elucidated.A lung cancer xenograft mouse model was established by subcutaneously injecting LLC cells into C57BL/6 mice. The tumor-bearing mice were exposed to either normoxia or intermittent hypoxia and received either IgG2a, anti-programmed death ligand-1 (PD-L1), PX-478, or anti-PD-L1 + PX-478 treatment.A significant upregulation of tumor associated macrophages (TAMs) papulation and PD-L1 levels was observed in lung adenocarcinoma patients with OSA. We further confirmed that hypoxia-inducible factor-1 alpha (HIF-1α) regulates PD-L1 at transcriptional levels, mainly through binding to the hypoxia response element 4. Using a lung cancer xenograft mouse model, we observed that intermittent hypoxia exposed tumors grew faster and bigger with upregulated HIF-1α and PD-L1 expression, enhanced TAMs and Treg populations, and reduced cytotoxic T cells and cytokine secretion. Finally, we found a combination of PX-478 and anti-PD-L1 exerted an encouraging tumor inhibition effect compared to single treatment. Combination therapies based on HIF-1α and PD-L1 blockade might serve as a promising strategy to treat lung cancer patients with OSA.
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