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Inhibition of galectin‐3 augments the antitumor efficacy of PD‐L1 blockade in non‐small‐cell lung cancer
FEBS Open Bio ( IF 2.8 ) Pub Date : 2021-01-17 , DOI: 10.1002/2211-5463.13088
Hongxin Zhang 1 , Pengfei Liu 2 , Yan Zhang 3 , Lujun Han 3 , Zhihui Hu 3 , Ziqi Cai 4 , Jianhui Cai 1, 5
Affiliation  

Multiple clinical trials have shown that monoclonal antibodies (mAbs) against programmed death‐ligand 1 (PD‐1/PD‐L1) can benefit patients with lung cancer by increasing their progression‐free survival and overall survival. However, a significant proportion of patients do not respond to anti‐PD‐1/PD‐L1 mAbs. In the present study, we investigated whether galectin (Gal)‐3 inhibitors can enhance the antitumor effect of PD‐L1 blockade. Using the NSCLC‐derived cell line A549, we examined the expression of Gal‐3 in lung cancer cells under hypoxic conditions and investigated the regulatory effect of Gal‐3 on PD‐L1 expression, which is mediated by the STAT3 pathway. We also explored whether Gal‐3 inhibition can facilitate the cytotoxic effect of T cells induced by PD‐L1 blockade. The effects of combined use of a Gal‐3 inhibitor and PD‐L1 blockade on tumor growth and T‐cell function were also investigated, and we found that hypoxia increased the expression and secretion of Gal‐3 by lung cancer cells. Gal‐3 increased PD‐L1 expression via the upregulation of STAT3 phosphorylation, and administration of a Gal‐3 inhibitor enhanced the effect of PD‐L1 blockade on the cytotoxic activity of T cells against cancer cells in vitro. In a mouse xenograft model, the combination of a Gal‐3 inhibitor and PD‐L1 blockade synergistically suppressed tumor growth. Furthermore, the administration of a Gal‐3 inhibitor enhanced T‐cell infiltration and granzyme B release in tumors. Collectively, our results show that Gal‐3 increases PD‐L1 expression in lung cancer cells and that the administration of a Gal‐3 inhibitor as an adjuvant enhanced the antitumor activity of PD‐L1 blockade.

中文翻译:

抑制半乳糖凝集素 3 增强了 PD-L1 阻断剂在非小细胞肺癌中的抗肿瘤功效

多项临床试验表明,针对程序性死亡配体 1 (PD-1/PD-L1) 的单克隆抗体 (mAb) 可以通过提高肺癌患者的无进展生存期和总生存期而使他们受益。然而,很大一部分患者对抗 PD-1/PD-L1 mAb 没有反应。在本研究中,我们研究了半乳糖凝集素 (Gal)-3 抑制剂是否可以增强 PD-L1 阻断的抗肿瘤作用。使用NSCLC衍生的细胞系A549,我们检测了低氧条件下肺癌细胞中Gal-3的表达,并研究了Gal-3对由STAT3通路介导的PD-L1表达的调节作用。我们还探讨了抑制 Gal-3 是否可以促进 PD-L1 阻断诱导的 T 细胞的细胞毒性作用。还研究了联合使用 Gal-3 抑制剂和 PD-L1 阻断剂对肿瘤生长和 T 细胞功能的影响,我们发现缺氧会增加肺癌细胞对 Gal-3 的表达和分泌。Gal-3 通过上调 STAT3 磷酸化增加 PD-L1 表达,并且给予 Gal-3 抑制剂增强了 PD-L1 阻断对 T 细胞对癌细胞的细胞毒活性的影响体外。在小鼠异种移植模型中,Gal-3 抑制剂和 PD-L1 阻断剂的组合协同抑制肿瘤生长。此外,Gal-3 抑制剂的给药增强了肿瘤中 T 细胞的浸润和颗粒酶 B 的释放。总的来说,我们的结果表明,Gal-3 增加了肺癌细胞中 PD-L1 的表达,并且使用 Gal-3 抑制剂作为佐剂增强了 PD-L1 阻断的抗肿瘤活性。
更新日期:2021-03-04
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