Single-Cell RNA Sequencing Reveals Stromal Evolution into LRRC15+ Myofibroblasts as a Determinant of Patient Response to Cancer Immunotherapy
Single-Cell RNA Sequencing Reveals Stromal Evolution into LRRC15+ Myofibroblasts as a Determinant of Patient Response to Cancer Immunotherapy
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DOI：
10.1158/2159-8290.cd-19-0644
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发表时间：
2020-02-01
期刊：
影响因子：
28.2
通讯作者：
Turley, Shannon J.
中科院分区：
文献类型：
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作者：
Dominguez, Claudia X.;Mueller, Soren;Turley, Shannon J.
由于只有一小部分患者对癌症免疫治疗有反应，因此需要更好地了解整个肿瘤微环境。利用单细胞转录学，我们绘制了动物模型中胰腺导管腺癌(PDAC)进展过程中成纤维细胞的图景。我们鉴定了一组由转化生长因子β编程的肿瘤相关成纤维细胞(CAF)，并表达富含亮氨酸的重复序列包含15(LRRC15)蛋白。这些LRRC15(+)CAF环绕在肿瘤胰岛周围，在正常胰腺组织中缺失。来自22名PDAC患者的80,000个单个细胞以及70名患者的样本通过IHC证实了人类患者中LRRC15(+)CAF的存在。此外，对六种癌症类型的600多名患者进行的免疫治疗临床试验显示，LRRC15(+)CAF签名水平升高与抗PD-L1治疗反应差有关。这项工作对于靶向肿瘤微环境中的非免疫成分以提高癌症患者对免疫检查点阻断治疗的反应具有重要意义。标志：本研究描述了胰腺癌体内肿瘤演变过程中CAF的单细胞景观。在包括多个实体肿瘤实体的免疫治疗试验数据中，由转化生长因子β驱动的LRRC15-CAF谱系与不良结果相关，并代表了联合治疗的靶点。
With only a fraction of patients responding to cancer immunotherapy, a better understanding of the entire tumor microenvironment is needed. Using single-cell transcriptomics, we chart the fibroblastic landscape during pancreatic ductal adenocarcinoma (PDAC) progression in animal models. We identify a population of carcinoma-associated fibroblasts (CAF) that are programmed by TGF beta and express the leucine-rich repeat containing 15 (LRRC15) protein. These LRRC15(+) CAFs surround tumor islets and are absent from normal pancreatic tissue. The presence of LRRC15(+) CAFs in human patients was confirmed in >80,000 single cells from 22 patients with PDAC as well as by using IHC on samples from 70 patients. Furthermore, immunotherapy clinical trials comprising more than 600 patients across six cancer types revealed elevated levels of the LRRC15(+) CAF signature correlated with poor response to anti-PD-L1 therapy. This work has important implications for targeting nonimmune elements of the tumor microenvironment to boost responses of patients with cancer to immune checkpoint blockade therapy.SIGNIFICANCE: This study describes the single-cell landscape of CAFs in pancreatic cancer during in vivo tumor evolution. A TGF beta-driven, LRRC15-CAF lineage is associated with poor outcome in immunotherapy trial data comprising multiple solid-tumor entities and represents a target for combinatorial therapy.