Circular RNA drives resistance to anti-PD-1 immunotherapy by regulating the miR-30a-5p/SOX4 axis in non-small cell lung cancer

Jing Wu; Meng-Xuan Zhu; Ke-Sang Li; Ling Peng; Peng-Fei Zhang

doi:10.20517/cdr.2021.100

Circular RNA drives resistance to anti-PD-1 immunotherapy by regulating the miR-30a-5p/SOX4 axis in non-small cell lung cancer

Cancer Drug Resist. 2022 Mar 25;5(2):261-270. doi: 10.20517/cdr.2021.100. eCollection 2022.

Authors

Jing Wu^{1

2

3}, Meng-Xuan Zhu^{1

2

3}, Ke-Sang Li^{4

3}, Ling Peng⁵, Peng-Fei Zhang^{1

2}

Affiliations

¹ Department of Medical Oncology, Zhongshan Hospital, Fudan University, Shanghai 200032, China.
² Cancer Center, Zhongshan Hospital, Fudan University, Shanghai 200032, China.
³ Authors contributed equally.
⁴ Department of Hematology and Oncology, Hwa Mei Hospital, University of Chinese Academy of Sciences, Ningbo 315012, Zhejiang, China.
⁵ Department of Pulmonary and Critical Care Medicine, Zhejiang Provincial People's Hospital, Hangzhou 310014, Zhejiang, China.

Abstract

Aim: Circular RNAs are widely and abnormally expressed in human cancer cells, and they participate in cancer progression. However, they have rarely been investigated in the immune evasion of non-small cell lung cancer (NSCLC). Here, we elucidated the function and molecular mechanism of hsa_circ_0020714 in promoting the resistance to anti-PD-1 immunotherapy of NSCLC. Methods: The expression of hsa_circ_0020714 were examined by qRT-PCR. In vivo experiments were executed to investigate the biological function of hsa_circ_0020714 in the sensitivity of NSCLC to anti-PD-1 immunotherapy. The qRT-PCR, fluorescence in situ hybridization, RNA pulldown, RNA immunoprecipitation, and western blot were carried out to investigate the potential regulatory mechanisms of hsa_circ_0020714 in NSCLC immune evasion. Results: The expression of hsa_circ_0020714 was upregulated in NSCLC tissues compared to the paired adjacent non-tumor tissues, and an increased expression of hsa_circ_0020714 was significantly associated with a bad prognosis and resistance to anti-PD-1 immunotherapy in patients with NSCLC. Mechanistically, hsa_circ_0020714 functions as an endogenous miR-30a-5p sponge to enhance SOX4 expression, thereby promoting immune evasion and anti-PD-1 resistance in NSCLC patients. Conclusion: Hsa_circ_0020714 induces the immune evasion and resistance to anti-PD-1 immunotherapy of NSCLC via the miR-30a-5p/SOX4 axis, and may be an promising immunotherapeutic target in NSCLC.

Keywords: NSCLC; PD-1; circRNAs; immune evasion; immunotherapy resistance.