细胞外基质刚度诱导CCL5合成以提高非小细胞肺癌免疫治疗响应

Extracellular matrix stiffness induces CCL5 synthesis to enhance immunotherapy response in non-small cell lung cancer

目的探讨非小细胞肺癌(non-small cell lung cancer,NSCLC)细胞外基质刚度调控趋化因子配体5(C-C motif chemokine ligand 5,CCL5)的机制,揭示CCL5对NSCLC的免疫治疗响应的影响。方法通过TCGA数据库分析NSCLC细胞外基质刚度与CCL5表达的相关性;根据NSCLC细胞外基质刚度设计不同刚度的聚丙烯酰胺水凝胶,获得响应水凝胶基质刚度力学加载的H1299细胞并对其进行转录组测序,利用q-PCR验证高基质刚度对CCL5表达的影响;进一步利用NSCLC患者转录组数据探究CCL5与免疫治疗响应的相关性。结果高细胞外基质刚度可以上调CCL5的表达,并且干扰素-γ(interferonγ,IFN-γ)介导的信号通路可能参与了该过程;CCL5高表达的NSCLC患者,肿瘤组织中细胞毒性T细胞的丰度更高,与抗程序性死亡受体-1(programmed cell death protein 1,PD-1)治疗响应性有关。结论细胞外基质刚度增加可促进CCL5合成,CCL5可通过增加肿瘤组织中细胞毒性T细胞浸润提升NSCLC的免疫治疗响应性。

Objective To investigate the mechanism of C-C motif chemokine ligand 5(CCL5)modulation by extracellular matrix stiffness in non-small cell lung cancer(NSCLC)and to determine the effect of CCL5 on the immunotherapy response of NSCLC.Methods The correlation between extracellular matrix stiffness and CCL5 expression in NSCLC was analyzed with the TCGA database.Polyacrylamide hydrogels with different stiffness were designed according to the extracellular matrix stiffness of NSCLC,and H1299 cells responding to the mechanical loading of hydrogel matrix stiffness were subjected to transcriptome sequencing.High matrix stiffness was verified to promote the expression of CCL5 by using sequence.Results High extracellular matrix stiffness upregulated CCL5 expression,and interferon-γmediated signaling pathway might be involved in the process.NSCLC patients with high CCL5 expression had a greater abundance of cytotoxic T-cells in tumor tissue and reacted favorably to anti-programmed cell death protein 1 treatment.Conclusion Increased extracellular matrix stiffness promotes CCL5 synthesis,and CCL5 enhances immunotherapy responsiveness in NSCLC by increasing cytotoxic T cell infiltration in tumor tissue.