Genitourinary Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY.
Institute of Oncology, Sheba Medical Center, Ramat Gan, Israel.
J Clin Oncol. 2023 Jun 10;41(17):3225-3235. doi: 10.1200/JCO.22.02144. Epub 2023 Mar 16.
Immune checkpoint blockade (ICB) therapy has significantly improved clinical outcomes in bladder cancer. Identification of correlates of benefit is critical to select appropriate therapy for individual patients.
To reveal genetic variables associated with benefit from ICB, we performed whole-exome sequencing on tumor specimens from 88 patients with advanced bladder cancer treated with ICB.
We identified several genetic factors that correlated with progression-free and overall survival after ICB therapy including mutation, tumor mutational burden, intratumoral heterogeneity, the ratio of nonsynonymous to synonymous mutations in the immunopeptidome (immune dN/dS), and tumor cell purity. In addition, we noted that neutrophil-to-lymphocyte ratio and smoking history were negatively associated with overall survival. These genetic characteristics define four molecular subtypes demonstrating differential sensitivity to ICB. We validated the association of these four subtypes with clinical benefit from ICB in an independent cohort (IMvigor210). Finally, we showed that these molecular subtypes also correlate with outcome, although with distinct relationships, among patients not treated with ICB using The Cancer Genome Atlas (TCGA) bladder cancer cohort. Using parallel RNA sequencing data, the subtypes were also shown to correlate with immune infiltration and inflammation, respectively, in the IMvigor210 and TCGA cohorts.
Together, our study defines molecular subgroups of bladder cancer that influence benefit from ICB.
免疫检查点阻断（ICB）疗法显著改善了膀胱癌患者的临床结局。确定获益相关因素对于为个体患者选择适当的治疗方法至关重要。
为了揭示与 ICB 获益相关的遗传变量，我们对 88 名接受 ICB 治疗的晚期膀胱癌患者的肿瘤标本进行了全外显子组测序。
我们确定了几个与 ICB 治疗后无进展生存期和总生存期相关的遗传因素，包括 突变、肿瘤突变负担、肿瘤内异质性、免疫肽组中非同义突变与同义突变的比值（免疫 dN/dS）以及肿瘤细胞纯度。此外，我们注意到中性粒细胞与淋巴细胞比值和吸烟史与总生存期呈负相关。这些遗传特征定义了四个对 ICB 具有不同敏感性的分子亚型。我们在独立队列（IMvigor210）中验证了这四个亚型与 ICB 临床获益的关联。最后，我们表明，在未接受 ICB 治疗的患者中（使用 TCGA 膀胱癌队列），这些分子亚型与结局也存在关联，尽管存在不同的关系。利用平行 RNA 测序数据，在 IMvigor210 和 TCGA 队列中，这些亚型也分别与免疫浸润和炎症相关。
总之，我们的研究定义了影响 ICB 获益的膀胱癌分子亚群。
