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

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 TGF? 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 TGF? 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.

SUBMITTER: Grauel AL

PROVIDER: S-EPMC7725805 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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

Grauel Angelo L AL Nguyen Beverly B Ruddy David D Laszewski Tyler T Schwartz Stephanie S Chang Jonathan J Chen Julie J Piquet Michelle M Pelletier Marc M Yan Zheng Z Kirkpatrick Nathaniel D ND Wu Jincheng J deWeck Antoine A Riester Markus M Hims Matt M Geyer Felipe Correa FC Wagner Joel J MacIsaac Kenzie K Deeds James J Diwanji Rohan R Jayaraman Pushpa P Yu Yenyen Y Simmons Quincey Q Weng Shaobu S Raza Alina A Minie Brian B Dostalek Mirek M Chikkegowda Pavitra P Ruda Vera V Iartchouk Oleg O Chen Naiyan N Thierry Raphael R Zhou Joseph J Pruteanu-Malinici Iulian I Fabre Claire C Engelman Jeffrey A JA Dranoff Glenn G Cremasco Viviana V

Nature communications 20201209 1

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 m ...[more]

PMID: 33298926

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Project description:BackgroundThe family of TGF-? ligands is large and its members are involved in many different signaling processes. These signaling processes strongly differ in type with TGF-? ligands eliciting both sustained or transient responses. Members of the TGF-? family can also act as morphogen and cellular responses would then be expected to provide a direct read-out of the extracellular ligand concentration. A number of different models have been proposed to reconcile these different behaviours. We were interested to define the set of minimal modifications that are required to change the type of signal processing in the TGF-? signaling network.ResultsTo define the key aspects for signaling plasticity we focused on the core of the TGF-? signaling network. With the help of a parameter screen we identified ranges of kinetic parameters and protein concentrations that give rise to transient, sustained, or oscillatory responses to constant stimuli, as well as those parameter ranges that enable a proportional response to time-varying ligand concentrations (as expected in the read-out of morphogens). A combination of a strong negative feedback and fast shuttling to the nucleus biases signaling to a transient rather than a sustained response, while oscillations were obtained if ligand binding to the receptor is weak and the turn-over of the I-Smad is fast. A proportional read-out required inefficient receptor activation in addition to a low affinity of receptor-ligand binding. We find that targeted modification of single parameters suffices to alter the response type. The intensity of a constant signal (i.e. the ligand concentration), on the other hand, affected only the strength but not the type of the response.ConclusionsThe architecture of the TGF-? pathway enables the observed signaling plasticity. The observed range of signaling outputs to TGF-? ligand in different cell types and under different conditions can be explained with differences in cellular protein concentrations and with changes in effective rate constants due to cross-talk with other signaling pathways. It will be interesting to uncover the exact cellular differences as well as the details of the cross-talks in future work.

Dataset Information

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

Publications

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

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