Immunotherapy, especially anti-PD-1, is becoming a pillar of modern muscle-invasive bladder cancer (MIBC) treatment. However, the objective response rates (ORR) are relatively low due to the lack of precise biomarkers to select patients. Herein, the molecular subtype, tumor mutation burden (TMB), and CD8+ T cells were calculated by the gene expression and mutation profiles of MIBC patients. MIBC immunotypes were constructed using clustering analysis based on tumor mutation burden, CD8+ T cells, and molecular subtypes. Mutated genes, enriched functional KEGG pathways and GO terms, and co-expressed network-specific hub genes have been identified. We demonstrated that ORR of immunotype A patients identified by molecular subtype, CD8+ T cells, and TMB is about 36% predictable. PIK3CA , RB1 , FGFR3 , KMT2C , MACF1 , RYR2 , and EP300 are differentially mutated among three immunotypes. Pathways such as ECM-receptor interaction, PI3K-Akt signaling pathway, and TGF-beta signaling pathway are top-ranked in enrichment analysis. Low expression of ACTA2 was associated with the MIBC survival benefit. The current study constructs a model that could identify suitable MIBC patients for immunotherapy, and it is an important step forward to the personalized treatment of bladder cancers.

中文翻译：

---

通过引入肿瘤突变负荷、CD8+ T 细胞和分子亚型来定义肌肉浸润性膀胱癌免疫型


免疫疗法，尤其是抗 PD-1 疗法，正在成为现代肌层浸润性膀胱癌 (MIBC) 治疗的支柱。然而，由于缺乏精确的生物标志物来选择患者，客观缓解率（ORR）相对较低。在此，通过 MIBC 患者的基因表达和突变谱计算分子亚型、肿瘤突变负荷 (TMB) 和 CD8+ T 细胞。 MIBC 免疫型是使用基于肿瘤突变负荷、CD8+ T 细胞和分子亚型的聚类分析构建的。突变基因、丰富的功能 KEGG 通路和 GO 术语以及共表达的网络特定中心基因已被识别。我们证明，通过分子亚型、CD8+ T 细胞和 TMB 鉴定的免疫 A 型患者的 ORR 的可预测性约为 36%。 PIK3CA 、RB1 、FGFR3 、KMT2C 、MACF1 、RYR2 和 EP300 在三种免疫型之间存在差异突变。 ECM-受体相互作用、PI3K-Akt信号通路和TGF-β信号通路等通路在富集分析中排名靠前。 ACTA2 的低表达与 MIBC 生存获益相关。目前的研究构建了一个模型，可以识别适合免疫治疗的 MIBC 患者，这是膀胱癌个体化治疗的重要一步。