A blood-based miRNA signature with prognostic value for overall survival in advanced stage non-small cell lung cancer treated with immunotherapy

Abstract

Immunotherapies have recently gained traction as highly effective therapies in a subset of late-stage cancers. Unfortunately, only a minority of patients experience the remarkable benefits of immunotherapies, whilst others fail to respond or even come to harm through immune-related adverse events. For immunotherapies within the PD-1/PD-L1 inhibitor class, patient stratification is currently performed using tumor (tissue-based) PD-L1 expression. However, PD-L1 is an accurate predictor of response in only ~30% of cases. There is pressing need for more accurate biomarkers for immunotherapy response prediction. We sought to identify peripheral blood biomarkers, predictive of response to immunotherapies against lung cancer, based on whole blood microRNA profiling. Using three well-characterized cohorts consisting of a total of 334 stage IV NSCLC patients, we have defined a 5 microRNA risk score (miRisk) that is predictive of overall survival following immunotherapy in training and independent validation (HR 2.40, 95% CI 1.37–4.19; P < 0.01) cohorts. We have traced the signature to a myeloid origin and performed miRNA target prediction to make a direct mechanistic link to the PD-L1 signaling pathway and PD-L1 itself. The miRisk score offers a potential blood-based companion diagnostic for immunotherapy that outperforms tissue-based PD-L1 staining.

Brief Report: A Blood-Based MicroRNA Complementary Diagnostic Predicts Immunotherapy Efficacy in Advanced-Stage NSCLC With High Programmed Death-Ligand 1 Expression

“…The miRisk score exploits these opportunities as a multivariable model that measures the expression of predominantly myeloid-derived miRNAs with predicted interactions with the PD-(L)1 signaling pathway. 5 This blood-based biomarker is found to have robust generalizable performance in a validation cohort for survival prediction after IO treatment (HR = 5.24, 95% CI: 2.17–12.66, p < 0.001) and utility as a complementary diagnostic for the decision to treat miRisk-high patients with ICT (HR = 0.35, 95% CI: 0.15–0.82, p = 0.018).…”

“…Sample processing and generation of small RNA expression profiles are described in detail in our previous work. 5 All anonymized small RNA sequencing data have been deposited at the European Nucleotide Archive under accession number PRJEB50502. Survival analyses were performed in Python (3.8.8), using the packages scikit-survival (version 0.15.1) 7 and Lifelines (version 0.26.0).…”

“…We previously reported the development of a circulating myeloid cell-derived 5 microRNA (miRNA) signature—5-miRNA risk score (miRisk)—to predict overall survival (OS) of patients with advanced NSCLC treated with IO in PD-L1 TPS unstratified patients. 5 Here, we systematically evaluated the ability of a revised miRisk score to identify PD-L1 high patients who are likely to benefit from chemotherapy in addition to immunotherapy.…”

Identifying tumor immunity-associated molecular features in liver hepatocellular carcinoma by multi-omics analysis

“…Furthermore, some studies have shown that miRNAs are useful in predicting the response to ICIs. For example, Rajakumar et al defined a 5-miRNA risk score which outperformed the tissue-based PD-L1 staining in predicting overall survival following immunotherapy in advanced NSCLC ( Rajakumar et al, 2022 ). Fan et al found that in NSCLC treated with anti-PD-1 antibody, miR-93, miR-138-5p, miR-200, miR-27a, miR-424, miR-34a, miR-28, miR-106b, miR-193a-3p, and miR-181a were significantly upregulated in responders versus non-responders ( Fan et al, 2020 ).…”

MicroRNAs and Drug Resistance in Non-Small Cell Lung Cancer: Where Are We Now and Where Are We Going

“…ICIs (e.g., Nivolumab, Pembrolizumab, Atezolizumab, and Durvalumab) have recently become the standard of care for patients with advanced NSCLC disease [ 160 ] thus opening a new era for the clinical management of metastatic patients. Change in the expression of selected miRNAs has been reported when plasma and serum of patients treated with either anti-PD1 or anti-PD-L1 antibodies have been investigated [ 161 , 162 , 163 , 164 , 165 , 166 ]. These preclinical studies highlighted the potential role of miRNAs as biomarkers predictive of response to ICIs.…”