Table_3_Immune-Associated Gene Signatures Serve as a Promising Biomarker of Immunotherapeutic Prognosis for Renal Clear Cell Carcinoma.docx

As the most common type of renal cell carcinoma (RCC), the renal clear cell carcinoma (ccRCC) is highly malignant and insensitive to chemotherapy or radiotherapy. Although systemic immunotherapies have been successfully applied to ccRCC in recent years, screening for patients who can benefit most from these therapies is still essential and challenging due to immunological heterogeneity of ccRCC patients. To this end, we implemented a series of deep investigation on the expression and clinic data of ccRCC from The Cancer Genome Atlas (TCGA) International Consortium for Cancer Genomics (ICGC). We identified a total of 946 immune-related genes that were differentially expressed. Among them, five independent genes, including SHC1, WNT5A, NRP1, TGFA, and IL4R, were significantly associated with survival and used to construct the immune-related prognostic differential gene signature (IRPDGs). Then the ccRCC patients were categorized into high-risk and low-risk subgroups based on the median risk score of the IRPDGs. IRPDGs subgroups displays distinct genomic and immunological characteristics. Known immunotherapy-related genes show different mutation burden, wherein the mutation rate of VHL was higher than 40% in the two IRPDGs subgroups, and SETD2 and BAP1 mutations differed most between two groups with higher frequency in the high-risk subgroup. Moreover, IRPDGs subgroups had different abundance in tumor-infiltrating immune cells (TIICs) with distinct immunotherapy efficacy. Plasma cells, regulatory cells (Tregs), follicular helper T cells (Tfh), and M0 macrophages were enriched in the high-risk group with a higher tumor immune dysfunction and rejection (TIDE) score. In contrast, the low-risk group had abundant M1 macrophages, mast cell resting and dendritic cell resting infiltrates with lower TIDE score and benefited more from immune checkpoint inhibitors (ICI) treatment. Compared with other biomarkers, such as TIDE and tumor inflammatory signatures (TIS), IRPDGs demonstrated to be a better biomarker for assessing the prognosis of ccRCC and the efficacy of ICI treatment with the promise in screening precise patients for specific immunotherapies.

作为肾细胞癌中最常见的类型，肾透明细胞癌（ccRCC）具有高度恶性和对化疗或放疗不敏感的特性。尽管近年来系统性免疫治疗已成功应用于ccRCC的治疗，但由于ccRCC患者的免疫异质性，筛选出能够从这些治疗中获益最大的患者仍至关重要且充满挑战。为此，我们对来自癌症基因组图谱（TCGA）和国际癌症基因组学联盟（ICGC）的ccRCC的表达和临床数据进行了深入的调查研究。我们共鉴定出946个差异表达的免疫相关基因。其中，包括SHC1、WNT5A、NRP1、TGFA和IL4R在内的五个独立基因与生存率显著相关，并用于构建免疫相关预后差异基因特征（IRPDGs）。然后，根据IRPDGs的中位风险评分，将ccRCC患者分为高风险和低风险亚组。IRPDGs亚组显示出独特的基因组学和免疫学特征。已知的免疫治疗相关基因表现出不同的突变负荷，其中VHL的突变率在两个IRPDGs亚组中均超过40%，而SETD2和BAP1突变在两组之间的差异最为显著，高风险亚组的突变频率更高。此外，IRPDGs亚组在肿瘤浸润免疫细胞（TIICs）中的丰度不同，具有不同的免疫治疗疗效。浆细胞、调节细胞（Tregs）、滤泡辅助T细胞（Tfh）和M0巨噬细胞在高风险组中富集，具有更高的肿瘤免疫功能障碍和排斥（TIDE）评分。相比之下，低风险组具有丰富的M1巨噬细胞、肥大细胞静息和树突状细胞静息浸润，TIDE评分较低，并从免疫检查点抑制剂（ICI）治疗中获益更多。与TIDE和肿瘤炎症特征（TIS）等其他生物标志物相比，IRPDGs显示出作为评估ccRCC预后和ICI治疗效果的更好生物标志物的潜力，并有望在筛选特定免疫治疗的精准患者中发挥作用。