Wan Huan, Xu Bin, Zhu Ni, Ren Baozhong
Department of Endocrinology, The Sixth Hospital of Wuhan, Affiliated Hospital of Jianghan University, Wuhan, Hubei Province, PR China.
Department of Oncology I, Renmin Hospital of Wuhan University, Wuhan, Hubei Province, PR China.
Tumori. 2020 Feb;106(1):55-63. doi: 10.1177/0300891619868287. Epub 2019 Aug 27.
The present study aims to investigate the efficacy and mechanisms of peroxisome proliferator-activated receptor γ coactivator 1-α agonist, as adjuvant to programmed death-1 (PD-1) blockade in hyporesponsive lung cancer cells-derived in vivo tumor model, using bezafibrate.
Mouse Lewis lung carcinoma (LLC) xenograft models were established and treated with programmed death-ligand 1 (PD-L1) monoclonal antibodies with or without bezafibrate. Tumors or peripheral blood of mice were harvested to investigate the quality, quantity, and function as well as energetic metabolism of cytotoxic T lymphocytes (CTLs) by flow cytometry or quantitative real-time polymerase chain reaction.
The combination of bezafibrate plus anti-PD-L1 reached synergistic tumoricidal effect in LLC xenograft mouse models, even though bezafibrate alone had no effect on tumor growth. Bezafibrate significantly facilitated CD8+ T cells infiltrating into tumor tissues by enhancing the expression of CXCL9 and CXCL10 within tumors as well as the receptor CXCR3 in infiltrating CTLs. Activated CTLs within tumors were also significantly upregulated by bezafibrate. Further data demonstrated that bezafibrate treatment could maintain the survival and functional capacity of tumor-infiltrating CTLs. Moreover, cellular reactive oxygen species in infiltrating CTLs and fatty acid oxidation (FAO)-related genes (PGC-1α, Cpt1a, and LCAD) expression within tumors were significantly increased after treatment with bezafibrate.
Bezafibrate synergized the tumoricidal effect of PD-1 blockade in hyporesponsive lung cancer by expansion of effector CTLs within tumor microenvironment. The potential mechanism may relate to the capacity of bezafibrate in regulating FAO of tumor-infiltrating CTLs.
本研究旨在使用苯扎贝特，探讨过氧化物酶体增殖物激活受体γ共激活因子1-α激动剂作为程序性死亡-1（PD-1）阻断剂辅助药物，在低反应性肺癌细胞来源的体内肿瘤模型中的疗效及机制。
建立小鼠Lewis肺癌（LLC）异种移植模型，并用或不用苯扎贝特的程序性死亡配体1（PD-L1）单克隆抗体进行治疗。采集小鼠的肿瘤或外周血，通过流式细胞术或定量实时聚合酶链反应研究细胞毒性T淋巴细胞（CTL）的质量、数量、功能以及能量代谢。
在LLC异种移植小鼠模型中，苯扎贝特加抗PD-L1联合用药达到了协同杀瘤效果，尽管单独使用苯扎贝特对肿瘤生长没有影响。苯扎贝特通过增强肿瘤内CXCL9和CXCL10的表达以及浸润CTL中受体CXCR3的表达，显著促进CD8+ T细胞浸润到肿瘤组织中。苯扎贝特还显著上调了肿瘤内活化的CTL。进一步的数据表明，苯扎贝特治疗可以维持肿瘤浸润CTL的存活和功能能力。此外，用苯扎贝特治疗后，浸润CTL中的细胞活性氧以及肿瘤内脂肪酸氧化（FAO）相关基因（PGC-1α、Cpt-1a和LCAD）的表达显著增加。
苯扎贝特通过在肿瘤微环境中扩增效应性CTL，增强了低反应性肺癌中PD-1阻断的杀瘤效果。潜在机制可能与苯扎贝特调节肿瘤浸润CTL的FAO能力有关。
