Zhao Qingqing, Wang Cong, Huang Wucui, Song Zhongquan, Lang Yang, Zhu Xiaoli
Department of Respiratory and Critical Care Medicine, Southeast University, Zhongda Hospital, Nanjing, 210009, China.
School of Medicine, Southeast University, Nanjing, 210009, China.
Heliyon. 2024 Sep 26;10(19):e38572. doi: 10.1016/j.heliyon.2024.e38572. eCollection 2024 Oct 15.
Small cell lung cancer (SCLC) is considered the most malignant subtype of lung cancer, and it has a restricted range of therapeutic choices. The emergence of immunotherapy has offered new possibilities for patients with SCLC. However, the scarcity of clinical specimens has hampered the progress of clinical studies and we still face a shortage of dependable indicators to forecast the effectiveness of immunotherapy for SCLC.
In our study, we assessed the ImmuneScore and StromalScore of 81 SCLC samples obtained from the cBioPortal database. By comparing gene expression differences between the high and low immune scores groups, we identified 24 differentially expressed genes. Subsequently, an intersection was performed with genes that exhibited differential expression between normal and SCLC tissues, leading us to isolate the gene CHRNA6. To gain a deeper insight into the possible significance of CHRNA6 in SCLC, we singled out 50 genes that showed the most pronounced positive and negative associations with its expression. We then pinpointed hub genes for subsequent functional enrichment analyses by establishing a protein-protein interactions network. We additionally assessed the link between CHRNA6 expression in SCLC and characteristics of the immune microenvironment, along with the efficacy of immunotherapy, using the CIBERSORT, immunophenoscores (IPS), and tumor immune dysfunction and exclusion (TIDE) algorithms. Furthermore, we confirmed the prognostic impact of CHRNA6 expression in SCLC patients undergoing immunotherapy within a clinical cohort. Lastly, we obtained data from The Cancer Genome Atlas (TCGA) to investigate CHRNA6 expression in various tumors and its associations with genetic alterations, DNA methylation, copy number variation, clinicopathological characteristics, biological processes, immune microenvironment, prognosis, and drug sensitivity.
In SCLC, we found that CHRNA6 function was associated with immune activation pathways such as antigen presentation processing and positive regulation of adaptive immune response, and that CHRNA6 demonstrated a strong correlation with immune cells infiltration. In addition, analysis of the clinical cohort revealed that patients with SCLC who exhibited elevated expression of CHRNA6 experienced better responses to immunotherapy. Our pan-cancer analysis disclosed that the expression of CHRNA6 is dysregulated in a multitude of cancers, potentially due to genetic mutations, copy number gains, and DNA demethylation. The gene set enrichment analysis (GSEA) outcomes indicated that CHRNA6 participates in immune responses and may play a positive immune regulatory role in most cancers. Furthermore, CHRNA6 has been observed to have a notable relationship with immune checkpoints, immunomodulators, immune cell infiltration, patient outcomes, and drug sensitivity across various cancers.
Our findings indicate that the CHRNA6 may act as a predictive indicator for SCLC patients receiving immunotherapy. The study also uncovers the aberrant expression of CHRNA6 in a range of human cancers and its potential roles in immunology and prognosis, offering novel perspectives for tailored cancer therapies.
小细胞肺癌（SCLC）被认为是肺癌中最具侵袭性的亚型，其治疗选择范围有限。免疫疗法的出现为SCLC患者提供了新的可能性。然而，临床样本的稀缺阻碍了临床研究的进展，我们仍然缺乏可靠的指标来预测SCLC免疫疗法的疗效。
在我们的研究中，我们评估了从cBioPortal数据库获得的81个SCLC样本的免疫评分（ImmuneScore）和基质评分（StromalScore）。通过比较高免疫评分组和低免疫评分组之间的基因表达差异，我们鉴定出24个差异表达基因。随后，将这些基因与正常组织和SCLC组织之间差异表达的基因进行交集分析，从而分离出CHRNA6基因。为了更深入了解CHRNA6在SCLC中的潜在意义，我们挑选出与其表达呈现最显著正相关和负相关的50个基因。然后，通过建立蛋白质-蛋白质相互作用网络确定枢纽基因，用于后续的功能富集分析。我们还使用CIBERSORT、免疫表型评分（IPS）和肿瘤免疫功能障碍与排除（TIDE）算法，评估了SCLC中CHRNA6表达与免疫微环境特征以及免疫疗法疗效之间的联系。此外，我们在一个临床队列中证实了CHRNA6表达对接受免疫疗法的SCLC患者的预后影响。最后，我们从癌症基因组图谱（TCGA）获取数据，以研究CHRNA6在各种肿瘤中的表达及其与基因改变、DNA甲基化、拷贝数变异、临床病理特征、生物学过程、免疫微环境、预后和药物敏感性的关系。
在SCLC中，我们发现CHRNA6的功能与免疫激活途径相关，如抗原呈递加工和适应性免疫反应的正调控，并且CHRNA6与免疫细胞浸润密切相关。此外，临床队列分析表明，CHRNA6表达升高的SCLC患者对免疫疗法的反应更好。我们的泛癌分析表明，CHRNA6在多种癌症中表达失调，可能是由于基因突变、拷贝数增加和DNA去甲基化所致。基因集富集分析（GSEA）结果表明，CHRNA6参与免疫反应，可能在大多数癌症中发挥积极的免疫调节作用。此外，在各种癌症中，CHRNA6与免疫检查点、免疫调节剂、免疫细胞浸润、患者预后和药物敏感性均存在显著关系。
我们的研究结果表明，CHRNA6可能作为接受免疫疗法的SCLC患者的预测指标。该研究还揭示了CHRNA6在一系列人类癌症中的异常表达及其在免疫学和预后方面的潜在作用，为个性化癌症治疗提供了新的视角。
