Department of Medical Oncology, Beijing Chest Hospital, Capital Medical University, Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing, China.
Clin Transl Oncol. 2022 Dec;24(12):2420-2431. doi: 10.1007/s12094-022-02913-9. Epub 2022 Aug 14.
Under the continuous stimulation of tumor antigen in the tumor microenvironment, CD8+T cells will enter a state of functional defect or failure, which cannot effectively prevent the progression of lung cancer. Therefore, finding potential targets for immunotherapy in lung cancer has broad prospects.
In the early stage of this study, the genes related to immune infiltration in lung cancer were found through the analysis on multiple datasets (GSE116959, GSE139032 and GSE111894). Characteristics of candidate genes were identified from transcriptome, methylation, single cell sequencing and other dimensions, respectively. Moreover, the correlation between candidate genes and immunotherapy-related genes and mutated genes of lung cancer was further identified. Finally, the expression of the candidate genes was detected with an online immunohistochemistry database.
According to the above research, it was found that CCL4 (chemokine (C-C motif) ligand 4) was abnormally highly expressed in samples from patients with NSCLC and had certain methylation characteristics. In addition, CCL4 was also closely associated with infiltration of immune cells, such as B cells and CD8+T cells. Interestingly, the aberrant expression of CCL4 affected the survival of CD8+T cells. Single cell sequencing results also showed that CCL4 was highly expressed in CD8+T cells and was involved in biological functions such as generation cycle. Finally, CCL4 expression was positively associated with PD-1 and PD-L1, and also with mutant genes, such as EGFR, ALK and ROS1, associated with the treatment for lung cancer.
CCL4 may be a potential target for immunotherapy in patients with NSCLC.
在肿瘤微环境中肿瘤抗原的持续刺激下，CD8+T 细胞会进入功能缺陷或衰竭状态，无法有效阻止肺癌的进展。因此，寻找肺癌免疫治疗的潜在靶点具有广阔的前景。
本研究早期通过对多个数据集（GSE116959、GSE139032 和 GSE111894）进行分析，找到与肺癌免疫浸润相关的基因。分别从转录组、甲基化、单细胞测序等多个维度鉴定候选基因的特征，进一步鉴定候选基因与免疫治疗相关基因和肺癌突变基因的相关性，最后利用在线免疫组化数据库检测候选基因的表达情况。
根据上述研究发现，CCL4（趋化因子（C-C 基序）配体 4）在 NSCLC 患者样本中异常高表达，且具有一定的甲基化特征。此外，CCL4 还与 B 细胞和 CD8+T 细胞等免疫细胞的浸润密切相关。有趣的是，CCL4 的异常表达会影响 CD8+T 细胞的存活。单细胞测序结果也表明，CCL4 在 CD8+T 细胞中高表达，并参与细胞生成周期等生物学功能。最后，CCL4 的表达与 PD-1 和 PD-L1 呈正相关，与 EGFR、ALK 和 ROS1 等与肺癌治疗相关的突变基因也存在相关性。
CCL4 可能是 NSCLC 患者免疫治疗的潜在靶点。
