Circular RNA hsa_circ_0000190 Facilitates the Tumorigenesis and Immune Evasion by Upregulating the Expression of Soluble PD-L1 in Non-Small-Cell Lung Cancer

Abstract

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.

The regulatory role and clinical application prospects of circRNA in the occurrence and development of CNS tumors

“…Recent research has reported that circRNAs could act as ceRNAs to modulate PD‐L1 expression, thereby regulating tumor immune escape in many tumors 164 . For instance, hsa_circ_0000190 promoted tumor immune evasion by boosting sPD‐L1 expression in non‐small‐cell lung cancer 165 . Researchers have proved that the inhabitation of IDO, CTLA‐4, and PD‐L1 interacted with increased Treg‐associated long‐term survival in gliomas 166 .…”

Current insight into the regulation of PD-L1 in cancer

“…Hsa_circ_0000190 enhances PD-L1 mRNA-mediated expression of soluble PD-L1 and promotes non-small cell lung carcinogenesis and immune evasion [ 86 ]. In addition, HasCircRNA-002178 is capable of enhancing PD-L1 expression by inducing T cell exhaustion via sponging miR-34 in LUAD cells [ 87 ].…”

“…MLL1 ↑PC [134] NRF2 ↑HCC [22] ATF3 ↑melanoma and NSCLC [55] Epigenetic regulation of PD-L1 DNA methylation ↓melanoma [62,64], leukemia [39] Histone modification ↓BC and B cell lymphomas [53,185], lung cancer [66] MicroRNAs shown in Table 1 N6-methyladenosine ↑OSCC [90], ↑BC [91] LncRNA and circRNA HOTTIP, SNHG12, EMX2OS-↑OC[76, 77, 81] SNHG20-↑esophagus cancer [78] CASC11-↑HCC [80] SNHG14-↑DLBCL [79] NUTM2A-AS1-↑GC [82] Hoxa-AS2-↑nasopharyngeal carcinoma [83] IFITM4P-↑OSCC [84] LncMX1-215-↓HNSCC [85] Hsa_circ_0000190-↑NSCLC [186] HasCircRNA-002178-↑ LUAD [87] CDR1-AS-↑CC [88] PD-L1 regulation at the protein level Ubiquitination ↓ BC [97], NSCLC [98], CC [99], colon cancer [100], melanoma [101,102,106], lung cancer [101], esophageal squamous cell carcinoma [105] Glycosylation ↑AML [108], TNBC [109,111], colon cancer [110], prostate cancer [111], glioma [112] Phosphorylation ↓ BC [114,116], HCC [115] Acetylation ↓ multiple cancers [117] Palmitoylation ↑ BC and colon cancer [118,…”

Current Landscape of Therapeutic Resistance in Lung Cancer and Promising Strategies to Overcome Resistance

“…Multiple types of circular RNAs (circRNAs), for instance, hsa_circ_0000190 [ 236 ], hsa_circ_0079587 [ 237 ], circFGFR1 [ 238 ], circUSP7 [ 239 ], etc., have been found to be associated with promoting tumor progression, metastasis, immune evasion, and immunotherapy resistance [ 235 ]. These circRNAs provoke resistance to anti-PD-1 therapy by upregulating PD-L1 expression, targeting CXCR4, and inhibiting the infiltration of CD8+ T cells, which supports the necessity of targeting circRNAs to resensitize tumor cells to immunotherapy.…”