Mao Shengqiang, Zeng Lingyan, Yang Ying, Liu Zhiqiang, Zhang Li
Department of Respiratory and Critical Care Medicine, Frontiers Science Center for Disease-related Molecular Network, Center of Precision Medicine, Precision Medicine Key Laboratory of Sichuan Province, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
Front Oncol. 2023 Apr 19;13:1170942. doi: 10.3389/fonc.2023.1170942. eCollection 2023.
Currently, programmed cell death-1 (PD-1)-targeted treatment is ineffective for a sizable minority of patients, and drug resistance still cannot be overcome.
To explore the mechanisms of immunotherapy and identify new therapeutic opportunities in lung adenocarcinoma (LUAD), data from patients who did and did not respond to the anti-PD-1 treatment were evaluated using single-cell RNA sequencing, and bulk RNA sequencing were collected.
We investigated the gene expression that respond or not respond to immunotherapy in diverse cell types and revealed transcriptional characteristics at the single-cell level. To ultimately explore the molecular response or resistance to anti-PD-1 therapy, cell-cell interactions were carried out to identify the different LRIs (ligand-receptor interactions) between untreated patients vs. no-responders, untreated patients vs. responders, and responders vs. non-responders. Next, two molecular subgroups were proposed based on 73 LRI genes, and subtype 1 had a poor survival status and was likely to be the immunosuppressive tumor subtype. Furthermore, based on the LASSO Cox regression analysis results, we found that , and can be distinct prognostic biomarkers, immune infiltration levels, and responses to immunotherapy in LUAD.
Altogether, the effects of immunotherapy were connected to LRIs scores, indicating that potential medications targeting these LRIs could contribute to the clinical benefit of immunotherapy. Our integrative omics analysis revealed the mechanisms underlying the anti-PD-1 therapy response and offered abundant clues for potential strategies to improve precise diagnosis and immunotherapy.
目前，程序性细胞死亡蛋白1（PD-1）靶向治疗对相当一部分患者无效，耐药性仍无法克服。
为了探索免疫治疗的机制并确定肺腺癌（LUAD）新的治疗机会，我们使用单细胞RNA测序对接受和未接受抗PD-1治疗的患者数据进行了评估，并收集了批量RNA测序数据。
我们研究了不同细胞类型中对免疫治疗有反应或无反应的基因表达，并揭示了单细胞水平的转录特征。为了最终探索对抗PD-1治疗的分子反应或耐药性，我们进行了细胞间相互作用分析，以确定未治疗患者与无反应者、未治疗患者与反应者以及反应者与无反应者之间不同的配体-受体相互作用（LRI）。接下来，基于73个LRI基因提出了两个分子亚组，亚组1的生存状态较差，可能是免疫抑制肿瘤亚型。此外，基于LASSO Cox回归分析结果，我们发现， ，以及 可以作为LUAD中不同的预后生物标志物、免疫浸润水平和免疫治疗反应指标。
总之，免疫治疗的效果与LRI评分相关，这表明针对这些LRI的潜在药物可能有助于免疫治疗的临床获益。我们的综合组学分析揭示了抗PD-1治疗反应的潜在机制，并为改善精准诊断和免疫治疗的潜在策略提供了丰富线索。
