m ⁶A 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

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 ⁶A) is a novel and decisive factor in tumour progression, chemotherapy resistance, and immunotherapy response. However, m ⁶A modification in SCLC remains poorly understood.

Methods

We systematically explored the molecular features and clinical significance of m ⁶A regulators in SCLC. We then constructed an m ⁶A regulator-based prognostic signature (m ⁶A 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 ⁶A 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 ⁶A regulators. Using the LASSO Cox model, a five-regulator-based ( G3BP1, METTL5, ALKBH5, IGF2BP3, and RBM15B) m ⁶A 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 ⁶A 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 ⁶A score to possess superior predictive power than other clinicopathological parameters. A multicentre multivariate analysis revealed the m ⁶A 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 ⁶A regulators in LS-SCLC. Our multicentre analysis found that the m ⁶A 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.