TGFβ-blockade uncovers stromal plasticity in tumors by revealing the existence of a subset of interferon-licensed fibroblasts

Angelo L. Grauel, Beverly Nguyen, David Ruddy, Tyler Laszewski, Stephanie Schwartz, Jonathan Chang, Julie Chen, Michelle Piquet, Marc Pelletier, Zheng Yan, Nathaniel D. Kirkpatrick, Jincheng Wu, Antoine deWeck, Markus Riester, Matt Hims, Felipe Correa Geyer, Joel Wagner, Kenzie MacIsaac, James Deeds, Rohan Diwanji, Pushpa Jayaraman, Yenyen Yu, Quincey Simmons, Shaobu Weng, Alina Raza, Brian Minie, Mirek Dostalek, Pavitra Chikkegowda, Vera Ruda, Oleg Iartchouk, Naiyan Chen, Raphael Thierry, Joseph Zhou, Iulian Pruteanu-Malinici, Claire Fabre, Jeffrey A. Engelman, Glenn Dranoff and Viviana Cremasco ()
Additional contact information
Angelo L. Grauel: Novartis Institutes for BioMedical Research
Beverly Nguyen: Novartis Institutes for BioMedical Research
David Ruddy: Novartis Institutes for BioMedical Research
Tyler Laszewski: Novartis Institutes for BioMedical Research
Stephanie Schwartz: Novartis Institutes for BioMedical Research
Jonathan Chang: Novartis Institutes for BioMedical Research
Julie Chen: Novartis Institutes for BioMedical Research
Michelle Piquet: Novartis Institutes for BioMedical Research
Marc Pelletier: Novartis Institutes for BioMedical Research
Zheng Yan: Novartis Institutes for BioMedical Research
Nathaniel D. Kirkpatrick: Novartis Institutes for BioMedical Research
Jincheng Wu: Novartis Institutes for BioMedical Research
Antoine deWeck: Novartis Institutes for BioMedical Research
Markus Riester: Novartis Institutes for BioMedical Research
Matt Hims: Novartis Institutes for BioMedical Research
Felipe Correa Geyer: Novartis Institutes for BioMedical Research
Joel Wagner: Novartis Institutes for BioMedical Research
Kenzie MacIsaac: Novartis Institutes for BioMedical Research
James Deeds: Novartis Institutes for BioMedical Research
Rohan Diwanji: Novartis Institutes for BioMedical Research
Pushpa Jayaraman: Novartis Institutes for BioMedical Research
Yenyen Yu: Novartis Institutes for BioMedical Research
Quincey Simmons: Novartis Institutes for BioMedical Research
Shaobu Weng: Novartis Institutes for BioMedical Research
Alina Raza: Novartis Institutes for BioMedical Research
Brian Minie: Novartis Institutes for BioMedical Research
Mirek Dostalek: Novartis Institutes for BioMedical Research
Pavitra Chikkegowda: Novartis Institutes for BioMedical Research
Vera Ruda: Novartis Institutes for BioMedical Research
Oleg Iartchouk: Novartis Institutes for BioMedical Research
Naiyan Chen: Novartis Institutes for BioMedical Research
Raphael Thierry: Novartis Institutes for BioMedical Research
Joseph Zhou: Novartis Institutes for BioMedical Research
Iulian Pruteanu-Malinici: Novartis Institutes for BioMedical Research
Claire Fabre: Novartis Institutes for BioMedical Research
Jeffrey A. Engelman: Novartis Institutes for BioMedical Research
Glenn Dranoff: Novartis Institutes for BioMedical Research
Viviana Cremasco: Novartis Institutes for BioMedical Research

Nature Communications, 2020, vol. 11, issue 1, 1-17

Abstract: Abstract 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.

Date: 2020
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DOI: 10.1038/s41467-020-19920-5

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