TGFβ-blockade uncovers stromal plasticity in tumors by revealing the existence of a subset of interferon-licensed fibroblasts.
TGFβ-blockade uncovers stromal plasticity in tumors by revealing the existence of a subset of interferon-licensed fibroblasts.
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TGFβ阻断通过揭示存在一部分经干扰素激活的成纤维细胞，揭示了肿瘤中的基质可塑性。
DOI：
10.1038/s41467-020-19920-5
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发表时间：
2020-12-09
影响因子：
16.6
通讯作者：
Cremasco V
中科院分区：
文献类型：
--
作者：
Grauel AL;Nguyen B;Ruddy D;Laszewski T;Schwartz S;Chang J;Chen J;Piquet M;Pelletier M;Yan Z;Kirkpatrick ND;Wu J;deWeck A;Riester M;Hims M;Geyer FC;Wagner J;MacIsaac K;Deeds J;Diwanji R;Jayaraman P;Yu Y;Simmons Q;Weng S;Raza A;Minie B;Dostalek M;Chikkegowda P;Ruda V;Iartchouk O;Chen N;Thierry R;Zhou J;Pruteanu-Malinici I;Fabre C;Engelman JA;Dranoff G;Cremasco V
尽管对靶向肿瘤微环境的基质成分的兴趣越来越大，但我们在开发适当的治疗剂以改变肿瘤基质景观方面仍然面临巨大挑战。这方面的一个主要障碍是我们对肿瘤中基质细胞的表型和功能异质性的认识不足。在此，我们对肿瘤间充质细胞进行了公正的询问，描绘了小鼠癌微环境中癌症相关成纤维细胞（CAF）的不同子集的共存，每个子集都具有独特的表型特征和功能。此外，我们的研究表明，体内TGFβ的中和导致CAF动力学的重塑，大大降低了肌成纤维细胞亚群的频率和活性，同时促进了成纤维细胞群体的形成，其特征在于对干扰素的强烈反应和增强的免疫调节特性。这些变化与生产性抗肿瘤免疫的发展和PD1免疫疗法的更大功效相关。沿着为临床环境中TGFβ和PD 1共阻断的评价提供了科学依据，本研究还支持肿瘤中基质细胞景观可塑性的概念，为旨在定义途径和分子以编程CAF组合物用于癌症治疗的未来研究奠定了基础。了解肿瘤微环境在其被用于治疗之前是很重要的。在这里，作者使用单细胞测序来研究小鼠肿瘤中的基质细胞，并鉴定抗TGF β治疗后出现的干扰素许可的癌症相关成纤维细胞的子集。
Despite the increasing interest in targeting stromal elements of the tumor microenvironment, we still face tremendous challenges in developing adequate therapeutics to modify the tumor stromal landscape. A major obstacle to this is our poor understanding of the phenotypic and functional heterogeneity of stromal cells in tumors. Herein, we perform an unbiased interrogation of tumor mesenchymal cells, delineating the co-existence of distinct subsets of cancer-associated fibroblasts (CAFs) in the microenvironment of murine carcinomas, each endowed with unique phenotypic features and functions. Furthermore, our study shows that neutralization of TGFβ in vivo leads to remodeling of CAF dynamics, greatly reducing the frequency and activity of the myofibroblast subset, while promoting the formation of a fibroblast population characterized by strong response to interferon and heightened immunomodulatory properties. These changes correlate with the development of productive anti-tumor immunity and greater efficacy of PD1 immunotherapy. Along with providing the scientific rationale for the evaluation of TGFβ and PD1 co-blockade in the clinical setting, this study also supports the concept of plasticity of the stromal cell landscape in tumors, laying the foundation for future investigations aimed at defining pathways and molecules to program CAF composition for cancer therapy. Understanding the tumor microenviroment is important before it can be exploited therapeutically. Here, the authors use single cell sequencing to study stromal cells in mouse tumors and identify a subset of interferon-licensed cancer associated fibroblasts that appear after anti-TGFβ treatment.
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影响因子：
28.2
作者：
Dominguez, Claudia X.;Mueller, Soren;Turley, Shannon J.
通讯作者：
Turley, Shannon J.
影响因子：
10.5
作者：
Coussens, LM;Raymond, WW;Hanahan, D
通讯作者：
Hanahan, D
DOI：
10.1073/pnas.1320318110
发表时间：
2013-12-10
影响因子：
11.1
作者：
Feig, Christine;Jones, James O.;Fearon, Douglas T.
通讯作者：
Fearon, Douglas T.
影响因子：
28.2
作者：
Elyada, Ela;Bolisetty, Mohan;Tuveson, David A.
通讯作者：
Tuveson, David A.
DOI：
10.1158/1078-0432.ccr-18-1955
发表时间：
2019-04-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Bernard V;Semaan A;Huang J;San Lucas FA;Mulu FC;Stephens BM;Guerrero PA;Huang Y;Zhao J;Kamyabi N;Sen S;Scheet PA;Taniguchi CM;Kim MP;Tzeng CW;Katz MH;Singhi AD;Maitra A;Alvarez HA
通讯作者：
Alvarez HA