m(6)A regulator expression profile predicts the prognosis, benefit of adjuvant chemotherapy, and response to anti-PD-1 immunotherapy in patients with small-cell lung cancer

BACKGROUND: Small cell lung cancer (SCLC) is lethal and possesses limited therapeutic options. Platinum-based chemotherapy—with or without immune checkpoint inhibitors (anti-PDs)—is the current first-line therapy for SCLCs; however, its associated outcomes are heterogeneous. N(6)-methyladenosine (m(6)A) is a novel and decisive factor in tumour progression, chemotherapy resistance, and immunotherapy response. However, m(6)A modification in SCLC remains poorly understood. METHODS: We systematically explored the molecular features and clinical significance of m(6)A regulators in SCLC. We then constructed an m(6)A regulator-based prognostic signature (m(6)A score) based on our examination of 256 cases with limited-stage SCLC (LS-SCLC) from three different cohorts—including an independent cohort that contained 150 cases with qPCR data. We additionally evaluated the relationships between the m(6)A score and adjuvant chemotherapy (ACT) benefits and the patients’ responses to anti-PD-1 treatment. Immunohistochemical (IHC) staining and the HALO digital pathological platform were used to calculate CD8+ T cell density. RESULTS: We observed abnormal somatic mutations and expressions of m(6)A regulators. Using the LASSO Cox model, a five-regulator-based (G3BP1, METTL5, ALKBH5, IGF2BP3, and RBM15B) m(6)A score was generated from the significant regulators to classify patients into high- and low-score groups. In the training cohort, patients with high scores had shorter overall survival (HR, 5.19; 2.75–9.77; P < 0.001). The prognostic accuracy of the m(6)A score was well validated in two independent cohorts (HR 4.6, P = 0.006 and HR 3.07, P < 0.001). Time-dependent ROC and C-index analyses found the m(6)A score to possess superior predictive power than other clinicopathological parameters. A multicentre multivariate analysis revealed the m(6)A score to be an independent prognostic indicator. Additionally, patients with low scores received a greater survival benefit from ACT, exhibited more CD8+ T cell infiltration, and were more responsive to cancer immunotherapy. CONCLUSIONS: Our results, for the first time, affirm the significance of m(6)A regulators in LS-SCLC. Our multicentre analysis found that the m(6)A score was a reliable prognostic tool for guiding chemotherapy and immunotherapy selections for patients with SCLC. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12916-021-02148-5.