Single-Cell Analysis Reveals Fibroblast Clusters Linked to Immunotherapy Resistance in Cancer
Single-Cell Analysis Reveals Fibroblast Clusters Linked to Immunotherapy Resistance in Cancer
复制标题
DOI：
10.1158/2159-8290.cd-19-1384
复制
发表时间：
2020-09-01
期刊：
影响因子：
28.2
通讯作者：
Mechta-Grigoriou, Fatima
中科院分区：
文献类型：
--
作者：
Kieffer, Yann;Hocine, Hocine R.;Mechta-Grigoriou, Fatima
一个癌症相关成纤维细胞亚群（FAP（+）/CAF-S1）介导乳腺癌中的免疫抑制，但其异质性及其对免疫治疗反应的影响尚不清楚。在这里，我们通过分析来自乳腺癌的19，000多个单个CAF-S1成纤维细胞来识别8个CAF-S1簇。我们通过流式细胞术和其他癌症类型的计算机分析验证了五个最丰富的簇，突出了它们的相关性。分别以细胞外基质蛋白和TGF β信号传导为特征的来自簇0和3的肌成纤维细胞指示对免疫疗法的原发性抗性。簇0/ecm-myCAF上调调节性T淋巴细胞（TCLB）中的PD-1和CTLA 4蛋白水平，这反过来增加CAF-S1簇3/TGF β-myCAF细胞含量。因此，我们的研究突出了特定CAF-S1簇和TGFs之间的正反馈回路，并揭示了它们在免疫治疗抵抗中的作用。意义：我们的工作为表征和理解癌症中的FAP（+）CAF提供了重大进展。我们在单细胞水平上达到了高分辨率，这使我们能够识别与免疫抑制和免疫治疗抗性相关的特定簇。簇特异性特征的鉴定为与免疫疗法组合的治疗选择铺平了道路。
A subset of cancer-associated fibroblasts (FAP(+)/CAF-S1) mediates immunosup- pression in breast cancers, but its heterogeneity and its impact on immunotherapy response remain unknown. Here, we identify 8 CAF-S1 clusters by analyzing more than 19,000 single CAF-S1 fibroblasts from breast cancer. We validate the five most abundant clusters by flow cytometry and in silico analyses in other cancer types, highlighting their relevance. Myofibroblasts from clusters 0 and 3, characterized by extracellular matrix proteins and TGF beta signaling, respectively, are indicative of primary resistance to immunotherapies. Cluster 0/ecm-myCAF upregulates PD-1 and CTLA4 protein levels in regulatory T lymphocytes (Tregs), which, in turn, increases CAF-S1 cluster 3/TGF beta-myCAF cellular content. Thus, our study highlights a positive feedback loop between specific CAF-S1 clusters and Tregs and uncovers their role in immunotherapy resistance.SIGNIFICANCE: Our work provides a significant advance in characterizing and understanding FAP(+) CAF in cancer. We reached a high resolution at single-cell level, which enabled us to identify specific clusters associated with immunosuppression and immunotherapy resistance. Identification of cluster-specific signatures paves the way for therapeutic options in combination with immunotherapies.