HIF-1α inhibition promotes the efficacy of immune checkpoint blockade in the treatment of non-small cell lung cancer
HIF-1α inhibition promotes the efficacy of immune checkpoint blockade in the treatment of non-small cell lung cancer
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DOI：
10.1016/j.canlet.2022.01.027
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发表时间：
2022-02-02
期刊：
影响因子：
9.7
通讯作者：
Zhang, Li
中科院分区：
文献类型：
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作者：
Luo, Fan;Lu, Fei-Teng;Zhang, Li
NSCLC 患者对免疫检查点抑制剂 (ICIs) 单药治疗的反应仍不令人满意。因此，将 ICI 与其他潜在治疗方式相结合对于增强单一药物的疗效具有重要意义。在这里，我们发现 HIF-1 α 抑制能够促进 NSCLC 的抗肿瘤免疫。我们应用 NSCLC 细胞系和小鼠模型来评估 HIF-1 α 抑制和 PD-1 联合阻断对肿瘤生长和肿瘤浸润淋巴细胞 (TIL) 功能的协同作用。利用公共数据集根据 HIF-1 α 和 LOXL2 的表达以及 EMT 相关标记物和 CD8(+) TIL 来研究患者的预后。此外，我们通过免疫组织化学探讨了 NSCLC 患者肿瘤样本中 HIF-1 α 和 LOXL2 水平与 CD8(+) TIL 之间的相关性，以及它们与患者生存的关系。在体外，PX-478（一种 HIF-1 α 抑制剂）与 ICI 联合使用时，可促进 T 细胞诱导的肿瘤细胞凋亡。此外，用 PX-478 和抗 PD-1 抗体治疗的小鼠表现出肿瘤生长明显延迟和生存时间延长，这与 TIL 和颗粒酶 B 分泌增加相关。此外，HIF-1α高表达的患者表现出高水平的EMT相关标志物和低TIL，表明免疫抑制表型。从机制上讲，我们观察到HIF-1α抑制抑制了缺氧诱导的EMT表型，并进一步减轻了肿瘤免疫抑制，这与阻断HIF-1α/LOXL2信号通路有关。总之，我们发现 HIF-1 α 抑制可以与抗 PD-1 协同作用，在体外和体内损害肿瘤生长。我们的数据表明，HIF-1 α 抑制剂是一种有前景的增强抗肿瘤免疫的治疗方法，并为临床上评估 ICI 与 HIF-1 α 抑制剂联合治疗 NSCLC 提供临床前依据。
The response to immune checkpoint inhibitors (ICIs) monotherapy remains unsatisfactory in patients with NSCLC. Thus, combining ICIs with other potential modalities is of great significance to enhance the response of single drug alone. Here, we identified that HIF-1 alpha inhibition was capable of promoting anti-tumor immunity in NSCLC. We applied NSCLC cell lines and mouse models to evaluate the synergy of combined HIF-1 alpha inhibition and PD-1 blockade on tumor growth and the function of tumor infiltrating lymphocytes (TILs). Public datasets were utilized to investigate patients' prognosis based on expressions of HIF-1 alpha and LOXL2 as well as EMT associated markers and CD8(+) TILs. Moreover, we explored the correlation between HIF-1 alpha and LOXL2 levels and CD8(+) TILs in tumor samples from patients with NSCLC by immunohistochemistry, as well as their association to patients' survival. In vitro, PX-478, an HIF-1 alpha inhibitor, promoted tumor cell apoptosis induced by T cells when combined with ICIs. Furthermore, mice treated with PX-478 and anti-PD-1 antibodies exhibited a marked delay in tumor growth and prolonged survival, which correlated with increased TILs and granzyme B secretion. Besides, patients with high HIF-1 alpha expression exhibited high levels of EMT-related markers and low TILs, indicating an immunosuppressive phenotype. Mechanistically, we observed that HIF-1 alpha inhibition suppressed the EMT phenotypes induced by hypoxia and further alleviated tumor immunosuppression, which was related to blockage of HIF-1 alpha/LOXL2 signaling pathway. In summary, we identified that HIF-1 alpha inhibition could synergize with anti-PD-1 to impair tumor growth in vitro and in vivo. Our data suggest that HIF-1 alpha inhibitors represent a promising treatment to enhance anti-tumor immunity and provide preclinical rationale to evaluate the combination of ICIs with HIF-1 alpha inhibition clinically in NSCLC.