Yu Qingxin, Zhang Facai, Feng Dechao, Li Dengxiong, Xia Yuhui, Gan Mei-Fu
Department of Pathology, Taizhou Hospital, Wenzhou Medical University, Linhai, China.
Department of Urology, Institute of Urology, West China Hospital, Sichuan University, Chengdu, China.
Front Genet. 2022 Aug 11;13:866696. doi: 10.3389/fgene.2022.866696. eCollection 2022.
Kidney renal clear cell carcinoma (KIRC) is an inflammation-related carcinoma, and inflammation has been recognized as an important factor in inducing carcinogenesis. To further explore the role of inflammation in KIRC, we developed an inflammation-related signature and verified its correlation with the tumor micro-environment. After the differential inflammation-related prognostic genes were screened by Lasso regression, the inflammation-related signature (IRS) was constructed based on the risk score of multivariate Cox regression. Then, the prognostic value of the IRS was evaluated by Kaplan-Meier analysis, receiver operating characteristic (ROC) curve analysis and multivariate Cox regression. Gene set variation analysis (GSVA) was applied to screen out enriched signaling pathways. Infiltrated immune cells, tumor mutational burden (TMB) and immune checkpoints were explored by CIBERSORTx and maftool. Four genes (TIMP1, PLAUR, CCL22, and IL15RA) were used to construct the IRS in patients with KIRC. Kaplan-Meier analysis and multivariate Cox regression identified that the IRS could independently predict the prognosis of patients with KIRC in the training and validation groups. The diagnostic value of the nomogram increased from 0.811 to 0.845 after adding the IRS to the multiparameter ROC analysis. The GSVA results indicated that IRS was closely related to primary immunodeficiency and antigen processing and presentation. The immune checkpoint LAG3 was highly expressed in patients with high-risk score ( < 0.05), while CD274 (PD-L1) and HAVCR2 were highly expressed in patients with low-risk score ( < 0.001). There was a significant positive correlation between the high-risk score group and CD8 T, activated CD4 memory T, gamma and delta regulatory T and M0 macrophage cells, while the low-risk score group was negatively associated with B memory, plasma, resting CD4 memory T, activated NK, M1 macrophages and resting mast cells. We found that the IRS might serve as a biomarker to predict the survival of KIRC. Moreover, patients with high or low-risk score might be sensitive to immune drugs at different immune checkpoints.
肾透明细胞癌（KIRC）是一种与炎症相关的癌症，炎症已被认为是诱导癌变的重要因素。为了进一步探究炎症在KIRC中的作用，我们开发了一种与炎症相关的特征，并验证了其与肿瘤微环境的相关性。通过Lasso回归筛选出差异炎症相关预后基因后，基于多变量Cox回归的风险评分构建了炎症相关特征（IRS）。然后，通过Kaplan-Meier分析、受试者工作特征（ROC）曲线分析和多变量Cox回归评估IRS的预后价值。应用基因集变异分析（GSVA）筛选出富集的信号通路。通过CIBERSORTx和maftool探索浸润免疫细胞、肿瘤突变负担（TMB）和免疫检查点。使用四个基因（TIMP1、PLAUR、CCL22和IL15RA）构建KIRC患者的IRS。Kaplan-Meier分析和多变量Cox回归表明，IRS可以在训练组和验证组中独立预测KIRC患者的预后。在多参数ROC分析中加入IRS后，列线图的诊断价值从０.８１１提高到０.８４５。GSVA结果表明，IRS与原发性免疫缺陷以及抗原加工和呈递密切相关。免疫检查点LAG3在高风险评分患者中高表达（<０.０５），而CD274（PD-L1）和HAVCR2在低风险评分患者中高表达（<０.００１）。高风险评分组与CD8 T细胞、活化的CD4记忆T细胞、γδ调节性T细胞和M0巨噬细胞之间存在显著正相关，而低风险评分组与B记忆细胞、浆细胞、静息CD4记忆T细胞、活化的NK细胞、M1巨噬细胞和静息肥大细胞呈负相关。我们发现，IRS可能作为预测KIRC患者生存的生物标志物。此外，高风险或低风险评分的患者可能对不同免疫检查点的免疫药物敏感。
