Department of Chest Medicine, Taipei Veterans General Hospital, Taipei 11217, Taiwan.
School of Medicine, National Yang Ming Chiao Tung University, Taipei 11221, Taiwan.
Int J Mol Sci. 2021 Dec 22;23(1):64. doi: 10.3390/ijms23010064.
Lung cancer is the leading cause of death from cancer in Taiwan and throughout the world. Immunotherapy has revealed promising and significant efficacy in NSCLC, through immune checkpoint inhibition by blocking programmed cell death protein (PD)-1/PD-1 ligand (PD-L1) signaling pathway to restore patients' T-cell immunity. One novel type of long, non-coding RNAs, circular RNAs (circRNAs), are endogenous, stable, and widely expressed in tissues, saliva, blood, urine, and exosomes. Our previous results revealed that the plasma level of hsa_circ_0000190 can be monitored by liquid-biopsy-based droplet digital PCR and may serve as a valuable blood-based biomarker to monitor the disease progression and the efficacy of immunotherapy. In this study, hsa_circ_0000190 was shown to increase the PD-L1 mRNA-mediated soluble PD-L1 (sPD-L1) expression, consequently interfering with the efficacy of anti-PD-L1 antibody and T-cell activation, which may result in immunotherapy resistance and poor outcome. Our results unraveled that hsa_circ_0000190 facilitated the tumorigenesis and immune evasion of NSCLC by upregulating sPD-L1 expression, potentially developing a different aspect in elucidating the molecular immunopathogenesis of NSCLC. Hsa_circ_0000190 upregulation can be an effective indicator for the progression of NSCLC, and hsa_circ_0000190 downregulation may possess a potential therapeutic value for the treatment of NSCLC in combination with immunotherapy.
肺癌是台湾乃至全球癌症死亡的主要原因。免疫疗法通过抑制程序性细胞死亡蛋白（PD）-1/PD-1 配体（PD-L1）信号通路，从而恢复患者的 T 细胞免疫，在非小细胞肺癌（NSCLC）中显示出有希望和显著的疗效。一种新型的长链非编码 RNA，环状 RNA（circRNA），是内源性的、稳定的，在组织、唾液、血液、尿液和外泌体中广泛表达。我们之前的结果表明，基于液体活检的液滴数字 PCR 可以监测 hsa_circ_0000190 的血浆水平，并且可能作为一种有价值的基于血液的生物标志物来监测疾病进展和免疫疗法的疗效。在这项研究中，hsa_circ_0000190 被证明可以增加 PD-L1 mRNA 介导的可溶性 PD-L1（sPD-L1）表达，从而干扰抗 PD-L1 抗体和 T 细胞的激活，这可能导致免疫疗法耐药和预后不良。我们的结果表明，hsa_circ_0000190 通过上调 sPD-L1 表达促进 NSCLC 的肿瘤发生和免疫逃逸，可能为阐明 NSCLC 的分子免疫发病机制提供一个新的研究方向。hsa_circ_0000190 的上调可能是 NSCLC 进展的有效指标，而下调 hsa_circ_0000190 可能具有与免疫疗法联合治疗 NSCLC 的潜在治疗价值。
