Table2_MHC-II Signature Correlates With Anti-Tumor Immunity and Predicts anti-PD-L1 Response of Bladder Cancer.XLSX

A large proportion of anti-tumor immunity research is focused on major histocompatibility complex class I (MHC-I) molecules and CD8+ T cells. Despite mounting evidence has shown that CD4+ T cells play a major role in anti-tumor immunity, the role of the MHC-II molecules in tumor immunotherapy has not been thoroughly researched and reported. In this study, we defined a MHC-II signature for the first time by calculating the enrichment score of MHC-II protein binding pathway with a single sample gene set enrichment analysis (ssGSEA) algorithm. To evaluate and validate the predictive value of the MHC class II (MHC-II) signature, we collected the transcriptome, mutation data and matched clinical data of bladder cancer patients from IMvigor210, The Cancer Genome Atlas (TCGA) databases and Gene Expression Omnibus (GEO) databases. Comprehensive analyses of immunome, transcriptome, metabolome, genome and drugome were performed in order to determine the association of MHC-II signature and tumor immunotherapy. We identified that MHC-II signature is an independent and favorable predictor of immune response and the prognosis of bladder cancer treated with immune checkpoint inhibitors (ICIs), one that may be superior to tumor mutation burden. MHC-II signature was significantly associated with increased immune cell infiltration and levels of immune-related gene expression signatures. Additionally, transcriptomic analysis showed immune activation in the high-MHC-II signature subgroup, whereas it showed fatty acid metabolism and glucuronidation in the low-MHC-II signature subgroup. Moreover, exploration of corresponding genomic profiles highlighted the significance of tumor protein p53 (TP53) and fibroblast growth factor receptor 3 (FGFR3) alterations. Our results also allowed for the identification of candidate compounds for combined immunotherapy treatment that may be beneficial for patients with bladder cancer and a high MHC-II signature. In conclusion, this study provides a new perspective on MHC-II signature, as an independent and favorable predictor of immune response and prognosis of bladder cancer treated with ICIs.

抗肿瘤免疫研究的绝大多数焦点集中于主要组织相容性复合体I类（MHC-I）分子与CD8+ T细胞。尽管越来越多的证据表明CD4+ T细胞在抗肿瘤免疫中发挥核心作用，但MHC-II分子在肿瘤免疫治疗中的作用尚未得到充分研究与报道。本研究首次通过单样本基因集富集分析（ssGSEA）算法计算MHC-II蛋白结合通路的富集得分，构建了MHC-II特征基因集。为评估并验证MHC-II特征基因集的预测价值，我们从IMvigor210队列、癌症基因组图谱（TCGA）数据库及基因表达综合数据库（GEO）中收集了膀胱癌患者的转录组、突变数据及匹配的临床资料。为明确MHC-II特征基因集与肿瘤免疫治疗的关联，本研究开展了免疫组学、转录组学、代谢组学、基因组学及药物基因组学的综合分析。研究发现，MHC-II特征基因集是膀胱癌患者接受免疫检查点抑制剂（ICIs）治疗后免疫应答与预后的独立优良预测因子，其预测效能或优于肿瘤突变负荷。MHC-II特征基因集与免疫细胞浸润程度升高及免疫相关基因表达特征水平上调显著相关。此外，转录组分析显示，高MHC-II特征基因集亚组呈现免疫激活状态，而低MHC-II特征基因集亚组则富集脂肪酸代谢与葡萄糖醛酸化通路。对相应基因组特征的深入分析凸显了肿瘤蛋白p53（TP53）与成纤维细胞生长因子受体3（FGFR3）变异的重要意义。本研究结果还筛选出可用于联合免疫治疗的候选化合物，或可惠及MHC-II特征基因集高表达的膀胱癌患者。综上，本研究为MHC-II特征基因集作为膀胱癌免疫检查点抑制剂治疗后免疫应答与预后的独立优良预测因子提供了全新视角。