Ahluwalia Pankaj, Ahluwalia Meenakshi, Mondal Ashis K, Sahajpal Nikhil, Kota Vamsi, Rojiani Mumtaz V, Rojiani Amyn M, Kolhe Ravindra
Department of Pathology, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA.
Department of Medicine, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA.
Cancers (Basel). 2021 Jan 5;13(1):155. doi: 10.3390/cancers13010155.
Lung cancer is one of the leading causes of death worldwide. Cell death pathways such as autophagy, apoptosis, and necrosis can provide useful clinical and immunological insights that can assist in the design of personalized therapeutics. In this study, variations in the expression of genes involved in cell death pathways and resulting infiltration of immune cells were explored in lung adenocarcinoma (The Cancer Genome Atlas: TCGA, lung adenocarcinoma (LUAD), 510 patients). Firstly, genes involved in autophagy ( = 34 genes), apoptosis ( = 66 genes), and necrosis ( = 32 genes) were analyzed to assess the prognostic significance in lung cancer. The significant genes were used to develop the cell death index (CDI) of 21 genes which clustered patients based on high risk (high CDI) and low risk (low CDI). The survival analysis using the Kaplan-Meier curve differentiated patients based on overall survival (40.4 months vs. 76.2 months), progression-free survival (26.2 months vs. 48.6 months), and disease-free survival (62.2 months vs. 158.2 months) (Log-rank test, < 0.01). Cox proportional hazard model significantly associated patients in high CDI group with a higher risk of mortality (Hazard Ratio: H.R 1.75, 95% CI: 1.28-2.45, < 0.001). Differential gene expression analysis using principal component analysis (PCA) identified genes with the highest fold change forming distinct clusters. To analyze the immune parameters in two risk groups, cytokines expression ( = 265 genes) analysis revealed the highest association of and (> 1.5-fold, < 0.01) with the high-risk group. The microenvironment cell-population (MCP)-counter algorithm identified the higher infiltration of CD8+ T cells, macrophages, and lower infiltration of neutrophils with the high-risk group. Interestingly, this group also showed a higher expression of immune checkpoint molecules , , and T cell exhaustion genes , , , , , and ) ( < 0.01). Furthermore, functional enrichment analysis identified significant perturbations in immune pathways in the higher risk group. This study highlights the presence of an immunocompromised microenvironment indicated by the higher infiltration of cytotoxic T cells along with the presence of checkpoint molecules and T cell exhaustion genes. These patients at higher risk might be more suitable to benefit from PD-L1 blockade or other checkpoint blockade immunotherapies.
肺癌是全球主要死因之一。自噬、凋亡和坏死等细胞死亡途径能提供有用的临床和免疫学见解，有助于设计个性化治疗方案。在本研究中，我们在肺腺癌中探索了细胞死亡途径相关基因表达的变化以及由此导致的免疫细胞浸润情况（癌症基因组图谱：TCGA，肺腺癌（LUAD），510例患者）。首先，分析了自噬相关基因（34个基因）、凋亡相关基因（66个基因）和坏死相关基因（32个基因），以评估其在肺癌中的预后意义。利用这些显著基因构建了一个由21个基因组成的细胞死亡指数（CDI），并据此将患者分为高风险（高CDI）和低风险（低CDI）两组。采用Kaplan-Meier曲线进行生存分析，结果显示两组患者在总生存期（40.4个月对76.2个月）、无进展生存期（26.2个月对48.6个月）和无病生存期（62.2个月对158.2个月）方面存在差异（对数秩检验，P<0.01）。Cox比例风险模型显示，高CDI组患者的死亡风险显著更高（风险比：HR 1.75，95%置信区间：1.28 - 2.45，P<0.001）。通过主成分分析（PCA）进行的差异基因表达分析确定了变化倍数最高的基因，这些基因形成了不同的聚类。为了分析两个风险组中的免疫参数，细胞因子表达（265个基因）分析显示，IL-1β和IL-6与高风险组的关联性最强（变化倍数>1.5，P<0.01）。微环境细胞群体（MCP）-计数器算法表明，高风险组中CD8 + T细胞和巨噬细胞浸润较高，中性粒细胞浸润较低。有趣的是，该组还显示出免疫检查点分子PD-L1、PD-L2和T细胞耗竭基因LAG-3、TIM-3、TIGIT、2B4、CD160和BTLA的表达较高（P<0.01）。此外，功能富集分析发现高风险组的免疫途径存在显著扰动。本研究强调了细胞毒性T细胞较高浸润以及检查点分子和T细胞耗竭基因的存在所表明的免疫功能低下微环境的存在。这些高风险患者可能更适合从PD-L1阻断或其他检查点阻断免疫疗法中获益。
