Department of Radiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Medical Imaging, Shanghai, China.
Department of Cancer Center, Zhongshan Hospital, Fudan University, Shanghai, China.
Front Immunol. 2022 Apr 11;13:861328. doi: 10.3389/fimmu.2022.861328. eCollection 2022.
Clear cell renal cell carcinoma (ccRCC) is characterized by metabolic dysregulation and distinct immunological signatures. The interplay between metabolic and immune processes in the tumor microenvironment (TME) causes the complexity and heterogeneity of immunotherapy responses observed during ccRCC treatment. Herein, we initially identified two distinct metabolic subtypes (C1 and C2 subtypes) and immune subtypes (I1 and I2 subtypes) based on the occurrence of differentially expressed metabolism-related prognostic genes and immune-related components. Notably, we observed that immune regulators with upregulated expression actively participated in multiple metabolic pathways. Therefore, we further delineated four immunometabolism-based ccRCC subtypes (M1, M2, M3, and M4 subtypes) according to the results of the above classification. Generally, we found that high metabolic activity could suppress immune infiltration. Immunometabolism subtype classification was associated with immunotherapy response, with patients possessing the immune-inflamed, metabolic-desert subtype (M3 subtype) that benefits the most from immunotherapy. Moreover, differences in the shifts in the immunometabolism subtype after immunotherapy were observed in the responder and non-responder groups, with patients from the responder group transferring to subtypes with immune-inflamed characteristics and less active metabolic activity (M3 or M4 subtype). Immunometabolism subtypes could also serve as biomarkers for predicting immunotherapy response. To decipher the genomic and epigenomic features of the four subtypes, we analyzed multiomics data, including miRNA expression, DNA methylation status, copy number variations occurrence, and somatic mutation profiles. Patients with the M2 subtype possessed the highest VHL gene mutation rates and were more likely to be sensitive to sunitinib therapy. Moreover, we developed non-invasive radiomic models to reveal the status of immune activity and metabolism. In addition, we constructed a radiomic prognostic score (PRS) for predicting ccRCC survival based on the seven radiomic features. PRS was further demonstrated to be closely linked to immunometabolism subtype classification, immune score, and tumor mutation burden. The prognostic value of the PRS and the association of the PRS with immune activity and metabolism were validated in our cohort. Overall, our study established four immunometabolism subtypes, thereby revealing the crosstalk between immune and metabolic activities and providing new insights into personal therapy selection.
透明细胞肾细胞癌(ccRCC)的特征是代谢失调和独特的免疫特征。代谢和免疫过程在肿瘤微环境(TME)中的相互作用导致了在 ccRCC 治疗过程中观察到的免疫治疗反应的复杂性和异质性。在此,我们最初根据差异表达的代谢相关预后基因和免疫相关成分的发生,确定了两种不同的代谢亚型(C1 和 C2 亚型)和免疫亚型(I1 和 I2 亚型)。值得注意的是,我们观察到表达上调的免疫调节剂积极参与多种代谢途径。因此,我们根据上述分类结果进一步划分了基于免疫代谢的 ccRCC 四种亚型(M1、M2、M3 和 M4 亚型)。通常,我们发现高代谢活性会抑制免疫浸润。免疫代谢亚型分类与免疫治疗反应相关,具有免疫炎症、代谢荒漠亚型(M3 亚型)的患者最受益于免疫治疗。此外,在应答者和无应答者组中观察到免疫治疗后免疫代谢亚型变化的差异,来自应答者组的患者转移到具有免疫炎症特征和较少活性代谢的亚型(M3 或 M4 亚型)。免疫代谢亚型也可以作为预测免疫治疗反应的生物标志物。为了解析四种亚型的基因组和表观基因组特征,我们分析了多组学数据,包括 miRNA 表达、DNA 甲基化状态、拷贝数变异发生和体细胞突变谱。M2 亚型的患者具有最高的 VHL 基因突变率,并且更有可能对舒尼替尼治疗敏感。此外,我们开发了非侵入性的放射组学模型来揭示免疫活性和代谢的状态。此外,我们构建了基于七个放射组学特征的预测 ccRCC 生存的放射组学预后评分(PRS)。PRS 进一步被证明与免疫代谢亚型分类、免疫评分和肿瘤突变负荷密切相关。PRS 的预后价值以及 PRS 与免疫活性和代谢的相关性在我们的队列中得到了验证。总的来说,我们的研究建立了四种免疫代谢亚型,从而揭示了免疫和代谢活动之间的相互作用,并为个体化治疗选择提供了新的见解。