Molecular Features of Cancer-associated Fibroblast Subtypes and their Implication on Cancer Pathogenesis, Prognosis, and Immunotherapy Resistance.
Molecular Features of Cancer-associated Fibroblast Subtypes and their Implication on Cancer Pathogenesis, Prognosis, and Immunotherapy Resistance.
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DOI：
10.1158/1078-0432.ccr-20-4226
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发表时间：
2021-05-01
期刊：
影响因子：
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通讯作者：
Zheng D
中科院分区：
文献类型：
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作者：
Galbo PM Jr;Zang X;Zheng D
癌相关成纤维细胞（CAFs）是肿瘤微环境（TME）的重要组成部分，但缺乏对其分子特征和临床意义的系统研究。在这里，我们试图比较多种癌症类型的CAF，以确定CAF亚型中激活的关键分子通路，这可能有助于临床结果，疾病进展和免疫治疗耐药性。我们对来自黑色素瘤（MEL）、头颈部鳞状细胞癌（HNSC）和肺癌（LC）的CAF进行了综合分析，并确定了在每个CAF亚型中明显活跃的分子特征。鉴定了单个CAF亚型的基因特征，并用于研究亚型丰度与临床结果和免疫疗法抗性的关联。我们确定了六种癌症类型共有的CAF亚型（泛CAF），并揭示了区分它们的分子特征和遗传途径。有趣的是，这些CAF亚型表达不同的免疫抑制因子，如CXCL 12和CXLC 14，以及干细胞促进因子IL-6。此外，我们确定了CAF异质性的关键新转录驱动因子（MEF 2C，TWIST 1，NR 1H 3，RELB和FOXM 1）。此外，我们发现CAF亚型与不同的临床结果相关，并揭示了可能激活或抑制癌症进展或参与抗PD 1或抗PD-L1免疫治疗耐药性的关键分子途径。我们的研究确定了几种癌症类型共有的CAF亚型的分子特征，涉及可能受益于CAF亚型靶向治疗的癌症类型，并确定了与免疫治疗耐药性相关的特定CAF亚型。
Cancer associated fibroblasts (CAFs) are an important component of the tumor microenvironment (TME), but a systematic investigation of their molecular characteristics and clinical relevance are lacking. Here, we sought to compare CAFs across multiple cancer types to identify critical molecular pathways activated in CAF subtypes, which may contribute to clinical outcome, disease progression, and immunotherapy resistance. We performed integrated analysis of CAFs from melanoma (MEL), head and neck squamous cell carcinoma (HNSC), and lung cancer (LC), and identified the molecular characteristics that are distinctly active in each CAF subtype. Gene signatures for individual CAF subtypes were identified and used to study the association of subtype abundance with clinical outcome and immunotherapy resistance. We identified six CAF subtypes (pan-CAFs) shared across cancer types and uncovered the molecular characteristics and genetic pathways distinguishing them. Interestingly, these CAF subtypes express distinct immunosuppressive factors, such as CXCL12 and CXLC14, and stem-cell promoting factor IL-6. Additionally, we identified novel transcriptional drivers (MEF2C, TWIST1, NR1H3, RELB, and FOXM1) key to CAF heterogeneity. Furthermore, we showed that CAF subtypes were associated with different clinical outcomes and uncovered key molecular pathways that could activate or suppress cancer progression or were involved in resistance to anti-PD1 or anti-PD-L1 immunotherapy. Our study identifies the molecular characteristics of CAF subtypes shared across several cancer types, implicates cancer types that may benefit from CAF subtype targeted therapies, and identifies specific CAF subtypes associated with immunotherapy resistance.