Abstract

SChLAP1 is recently reported as a key oncogenic long non-coding RNA in human cancer. However, whether SChLAP1 functions in non-small cell lung cancer (NSCLC) and its specific potential regulatory mechanism remain unexplored. In this study, we found that depletion of SChLAP1 significantly inhibited NSCLC cell proliferation, migration and invasion in vitro, and retarded tumour growth and lung metastasis in vivo. SChLAP1 facilitated NSCLC cell immune evasion against CD8⁺ T cells through PD-1/PD-L1 immune checkpoint. In detail, SChLAP1 was able to directly interact with AUF1, antagonizing the binding between AUF1 and PDL1 mRNA 3′-UTR, resulting in increasing PDL1 mRNA stability and expression, thereby repressing CD8⁺ T cell function. Consistently, anti-PD-1/PD-L1 treatment evidently blocked the enhanced cell proliferation and invasion caused by SChLAP1 overexpression. Importantly, SChLAP1 was significantly upregulated in NSCLC cell lines, serum and tissues, which was identified as an excellent indicator for the diagnosis and prognosis of NSCLC. In conclusion, our data for the first time uncover that SChLAP1 functions an oncogene in NSCLC by promoting cancer cell immune evasion via regulating the AUF1/PDL1 axis, targeting of SChLAP1 may be a potential approach to improve the efficacy of immunotherapy in NSCLC patients.

摘要

SChLAP1 最近被报道为人类癌症中的关键致癌长非编码 RNA。然而，SChLAP1 是否在非小细胞肺癌 (NSCLC) 中发挥作用及其特定的潜在调控机制仍有待探索。在本研究中，我们发现 SChLAP1 的耗竭显着抑制了体外NSCLC 细胞的增殖、迁移和侵袭，并在体内延缓了肿瘤生长和肺转移。SChLAP1通过 PD-1/PD-L1 免疫检查点促进 NSCLC 细胞对 CD8 ^{+ T 细胞的免疫逃避。}具体而言，SChLAP1 能够直接与 AUF1 相互作用，拮抗 AUF1 与 PDL1 mRNA 3'-UTR 之间的结合，导致 PDL1 mRNA 稳定性和表达增加，从而抑制 CD8 ⁺T细胞功能。一致地，抗PD-1 / PD-L1治疗明显阻断了由SChLAP1过表达引起的增强的细胞增殖和侵袭。重要的是，SChLAP1 在 NSCLC 细胞系、血清和组织中显着上调，被认为是 NSCLC 诊断和预后的极好指标。总之，我们的数据首次揭示了 SChLAP1通过调节 AUF1/PDL1 轴促进癌细胞免疫逃避，从而在 NSCLC 中发挥致癌基因的作用，靶向 SChLAP1 可能是提高 NSCLC 患者免疫治疗疗效的潜在方法。