Single-cell analysis of pancreatic ductal adenocarcinoma identifies a novel fibroblast subtype associated with poor prognosis but better immunotherapy response.
Single-cell analysis of pancreatic ductal adenocarcinoma identifies a novel fibroblast subtype associated with poor prognosis but better immunotherapy response.
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胰腺导管腺癌的单细胞分析发现了一种新型成纤维细胞亚型，该亚型与预后不良但免疫治疗反应较好相关
DOI：
10.1038/s41421-021-00271-4
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发表时间：
2021-05-25
期刊：
影响因子：
33.5
通讯作者：
Wang L
中科院分区：
文献类型：
--
作者：
Wang Y;Liang Y;Xu H;Zhang X;Mao T;Cui J;Yao J;Wang Y;Jiao F;Xiao X;Hu J;Xia Q;Zhang X;Wang X;Sun Y;Fu D;Shen L;Xu X;Xue J;Wang L
目前胰腺导管腺癌(PDAC)的病理和分子分类为治疗方案提供了有限的指导，尤其是免疫治疗。肿瘤相关成纤维细胞(CAF)是PDAC中促结缔组织间质的主要参与者，调节肿瘤的进展和治疗反应。利用单细胞RNA测序技术，我们探讨了不同程度促结缔组织发育的PDAC患者肿瘤间的异质性。我们发现CAF、导管癌细胞和免疫细胞在极其密集和疏松类型的PDAC(致密型，高度结缔组织增生；疏松型，低促结缔组织增生)之间存在显著的肿瘤间异质性。值得注意的是，没有检测到CAF丰度的差异，但与密度型PDAC相比，在松散型PDAC中发现了一种新的具有高活性代谢状态(MeCAF)的CAF亚型。MeCAF具有高活性的糖酵解，而相应的癌细胞使用氧化磷酸化作为主要的代谢方式，而不是糖酵解。我们发现松散型PDAC的免疫细胞比例和活性明显高于致密型PDAC。然后，在我们的PDAC队列和公共数据库中进一步验证了CAF亚型的临床意义。MeCAF丰富的PDAC患者转移风险较高，预后较差，但对免疫治疗的反应明显较好(客观有效率64.71%，完全有效1例)。我们研究了致密型和疏松型PDAC之间细胞成分、免疫活性和代谢状态的肿瘤间异质性，并确定meCAF是一种新的CAF亚型，对PDAC的进展和免疫治疗的敏感性至关重要。
The current pathological and molecular classification of pancreatic ductal adenocarcinoma (PDAC) provides limited guidance for treatment options, especially for immunotherapy. Cancer-associated fibroblasts (CAFs) are major players of desmoplastic stroma in PDAC, modulating tumor progression and therapeutic response. Using single-cell RNA sequencing, we explored the intertumoral heterogeneity among PDAC patients with different degrees of desmoplasia. We found substantial intertumoral heterogeneity in CAFs, ductal cancer cells, and immune cells between the extremely dense and loose types of PDACs (dense-type, high desmoplasia; loose-type, low desmoplasia). Notably, no difference in CAF abundance was detected, but a novel subtype of CAFs with a highly activated metabolic state (meCAFs) was found in loose-type PDAC compared to dense-type PDAC. MeCAFs had highly active glycolysis, whereas the corresponding cancer cells used oxidative phosphorylation as a major metabolic mode rather than glycolysis. We found that the proportion and activity of immune cells were much higher in loose-type PDAC than in dense-type PDAC. Then, the clinical significance of the CAF subtypes was further validated in our PDAC cohort and a public database. PDAC patients with abundant meCAFs had a higher risk of metastasis and a poor prognosis but showed a dramatically better response to immunotherapy (64.71% objective response rate, one complete response). We characterized the intertumoral heterogeneity of cellular components, immune activity, and metabolic status between dense- and loose-type PDACs and identified meCAFs as a novel CAF subtype critical for PDAC progression and the susceptibility to immunotherapy.
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