Icahn Institute for Data Science and Genomics Technology, Icahn School of Medicine at Mount Sinai, New York, New York.
Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York.
Clin Cancer Res. 2021 Aug 1;27(15):4287-4300. doi: 10.1158/1078-0432.CCR-20-4574. Epub 2021 Apr 9.
To define dominant molecular and cellular features associated with PD-1/PD-L1 blockade resistance in metastatic urothelial cancer.
We pursued an unbiased approach using bulk RNA sequencing data from two clinical trials to discover (IMvigor 210) and validate (CheckMate 275) pretreatment molecular features associated with resistance to PD-1/PD-L1 blockade in metastatic urothelial cancer. We then generated single-cell RNA sequencing (scRNA-seq) data from muscle-invasive bladder cancer specimens to dissect the cellular composition underlying the identified gene signatures.
We identified an adaptive immune response gene signature associated with response and a protumorigenic inflammation gene signature associated with resistance to PD-1/PD-L1 blockade. The adaptive immune response:protumorigenic inflammation signature expression ratio, coined the 2IR score, best correlated with clinical outcomes, and was externally validated. Mapping these bulk gene signatures onto scRNA-seq data uncovered their underlying cellular diversity, with prominent expression of the protumorigenic inflammation signature by myeloid phagocytic cells. However, heterogeneity in expression of adaptive immune and protumorigenic inflammation genes was observed among single myeloid phagocytic cells, quantified as the myeloid single cell immune:protumorigenic inflammation ratio (M2IR) score. Single myeloid phagocytic cells with low M2IR scores demonstrated upregulation of proinflammatory cytokines/chemokines and downregulation of antigen presentation genes, were unrelated to M1 versus M2 polarization, and were enriched in pretreatment blood samples from patients with PD-L1 blockade-resistant metastatic urothelial cancer.
The balance of adaptive immunity and protumorigenic inflammation in individual tumor microenvironments is associated with PD-1/PD-L1 resistance in urothelial cancer with the latter linked to a proinflammatory cellular state of myeloid phagocytic cells detectable in tumor and blood..
确定与转移性尿路上皮癌中 PD-1/PD-L1 阻断耐药相关的主要分子和细胞特征。
我们采用无偏倚的方法，使用来自两项临床试验的 bulk RNA 测序数据，发现（IMvigor 210）并验证（CheckMate 275）与转移性尿路上皮癌中 PD-1/PD-L1 阻断耐药相关的预处理分子特征。然后，我们从肌肉浸润性膀胱癌标本中生成单细胞 RNA 测序（scRNA-seq）数据，以剖析鉴定基因特征背后的细胞组成。
我们确定了与反应相关的适应性免疫反应基因特征和与 PD-1/PD-L1 阻断耐药相关的促肿瘤炎症基因特征。适应性免疫反应：促肿瘤炎症特征表达比，命名为 2IR 评分，与临床结局相关性最佳，并进行了外部验证。将这些 bulk 基因特征映射到 scRNA-seq 数据上，揭示了它们潜在的细胞多样性，其中髓样吞噬细胞中促肿瘤炎症特征的表达最为突出。然而，在单个髓样吞噬细胞中观察到适应性免疫和促肿瘤炎症基因的表达存在异质性，用髓样单细胞免疫：促肿瘤炎症比（M2IR）评分来量化。具有低 M2IR 评分的单个髓样吞噬细胞表现出促炎细胞因子/趋化因子的上调和抗原呈递基因的下调，与 M1 与 M2 极化无关，并且在 PD-L1 阻断耐药转移性尿路上皮癌患者的预处理血液样本中富集。
个体肿瘤微环境中适应性免疫和促肿瘤炎症的平衡与尿路上皮癌中的 PD-1/PD-L1 耐药相关，后者与髓样吞噬细胞中可检测到的促炎细胞状态相关。
