m⁶A regulator expression profile predicts the prognosis, benefit of adjuvant chemotherapy, and response to anti-PD-1 immunotherapy in patients with small-cell lung cancer.

Abstract

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. N⁶-methyladenosine (m⁶A) is a novel and decisive factor in tumour progression, chemotherapy resistance, and immunotherapy response. However, m⁶A modification in SCLC remains poorly understood. We systematically explored the molecular features and clinical significance of m⁶A regulators in SCLC. We then constructed an m⁶A regulator-based prognostic signature (m⁶A 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 m⁶A 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. We observed abnormal somatic mutations and expressions of m⁶A regulators. Using the LASSO Cox model, a five-regulator-based (G3BP1, METTL5, ALKBH5, IGF2BP3, and RBM15B) m⁶A 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 m⁶A 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 m⁶A score to possess superior predictive power than other clinicopathological parameters. A multicentre multivariate analysis revealed the m⁶A 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. Our results, for the first time, affirm the significance of m⁶A regulators in LS-SCLC. Our multicentre analysis found that the m⁶A score was a reliable prognostic tool for guiding chemotherapy and immunotherapy selections for patients with SCLC.