Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China.
Department of Pathology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China.
BMC Med. 2021 Nov 22;19(1):284. doi: 10.1186/s12916-021-02148-5.
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-methyladenosine (mA) is a novel and decisive factor in tumour progression, chemotherapy resistance, and immunotherapy response. However, mA modification in SCLC remains poorly understood.
We systematically explored the molecular features and clinical significance of mA regulators in SCLC. We then constructed an mA regulator-based prognostic signature (mA 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 mA 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 mA regulators. Using the LASSO Cox model, a five-regulator-based (G3BP1, METTL5, ALKBH5, IGF2BP3, and RBM15B) mA 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 mA 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 mA score to possess superior predictive power than other clinicopathological parameters. A multicentre multivariate analysis revealed the mA 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 mA regulators in LS-SCLC. Our multicentre analysis found that the mA score was a reliable prognostic tool for guiding chemotherapy and immunotherapy selections for patients with SCLC.
小细胞肺癌（SCLC）是致命的，且治疗选择有限。铂类化疗联合或不联合免疫检查点抑制剂（抗 PD 治疗）是目前 SCLC 的一线治疗方法；然而，其相关疗效存在异质性。N6-甲基腺苷（m6A）是肿瘤进展、化疗耐药和免疫治疗反应的一个新的决定性因素。然而，SCLC 中的 m6A 修饰仍知之甚少。
我们系统地研究了 SCLC 中 m6A 调节因子的分子特征和临床意义。然后，我们基于对三个不同队列（包括包含 150 例 qPCR 数据的独立队列）中 256 例局限期 SCLC（LS-SCLC）的检查，构建了一个基于 m6A 调节因子的预后评分（m6A 评分）。我们还评估了 m6A 评分与辅助化疗（ACT）获益以及患者对抗 PD-1 治疗的反应之间的关系。免疫组化（IHC）染色和 HALO 数字病理平台用于计算 CD8+T 细胞密度。
我们观察到异常的体细胞突变和 m6A 调节因子的表达。使用 LASSO Cox 模型，从显著的调节因子中生成了一个由五个调节因子（G3BP1、METTL5、ALKBH5、IGF2BP3 和 RBM15B）组成的 m6A 评分，以将患者分为高分组和低分组。在训练队列中，高分组患者的总生存期更短（HR，5.19；2.75-9.77；P<0.001）。m6A 评分在两个独立队列中的验证准确性良好（HR 4.6，P=0.006 和 HR 3.07，P<0.001）。时间依赖性 ROC 和 C 指数分析发现，m6A 评分具有优于其他临床病理参数的预测能力。多中心多变量分析表明，m6A 评分是一个独立的预后指标。此外，低分组患者从 ACT 中获得更大的生存获益，表现出更多的 CD8+T 细胞浸润，对癌症免疫治疗更敏感。
我们的研究结果首次证实了 m6A 调节因子在 LS-SCLC 中的意义。我们的多中心分析发现，m6A 评分是一种可靠的预后工具，可指导 SCLC 患者的化疗和免疫治疗选择。
