TGFβ-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 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.

The Biological and Biomechanical Role of Transglutaminase-2 in the Tumour Microenvironment

“…Of these factors, TGF-β appears to be particularly important. Cancer-secreted TGF-β is capable of inducing CAF phenotype [ 111 , 112 , 113 ], and TGF-β signalling in CAFs is closely linked to poor clinical outcome [ 94 , 114 ], with inhibition leading to remodelling of CAF dynamics, better immune response, and disease regression in in vitro models. The well-established link between TG2 and TGF-β is therefore critical, with TGF-β upregulating TG2, while TG2 is also known to be capable of transforming inactive TGF-β to its active form [ 115 , 116 , 117 ].…”

Tumor Cells and Cancer-Associated Fibroblasts: An Updated Metabolic Perspective

“…Indeed, FAP High CAF-S1 are able to attract, retain, increase the survival of CD4+ CD25+ T lymphocytes and promote their differentiation into regulatory T cells (Treg) [ 133 , 134 , 154 ]. In line with the identification of several subsets among FAP High CAF-S1, recent data has demonstrated that only specific ones, characterized by ECM accumulation, wound-healing signature and TGFβ-signaling, are associated with an immunosuppressive tumor environment [ 139 , 141 , 142 , 155 ]. In particular, ecm-myCAF and TGFβ-myCAF cellular clusters are correlated with the content in FOXP3 + T lymphocytes in breast cancer, and are able to increase PD-1 and CTLA-4 protein levels at the surface of FOXP3 high Tregs [ 142 ].…”

“…Interestingly, accumulation of ecm-myCAF, wound-myCAF and TGFβ-myCAF clusters is correlated with resistance to immunotherapy in melanoma and non-small cell lung cancer patients [ 142 ]. Moreover, TGFβ inhibition has been shown to reduce myofibroblast features, while increasing immunomodulatories properties in murine carcinomas, thereby providing the rationale of combining TGFβ and PD-1/PD-L1 in clinical settings [ 155 ]. All these data shed light on CAF heterogeneity within tumors, in particular on the FAP High CAF-S1 subset, and demonstrate their different functions in tumor progression, metastatic spread, immunosuppression and resistance to immunotherapies.…”

Actin Cytoskeleton and Regulation of TGFβ Signaling: Exploring Their Links

“…In the tumor microenvironment, stromal cells are an abundant source of TGFβ [ 78 ], with cancer-associated fibroblasts (CAFs) the most significant producers [ 79 , 80 ]. Activated TGFβ signaling leads to CAF activation, CAF-mediated cancer progression [ 81 ] and may differently influence CAF subsets [ 82 ].…”

“…Noteworthy, CAF-derived TGFβ may contribute to immunosurveillance and escape and may participate in therapy resistance, including immunotherapy with immune checkpoint blockade [ 83 , 84 , 85 ], also by excluding CD8+ T lymphocytes from the tumor site [ 86 , 87 ]. A recent paper suggests that TGFβ neutralization targets only selected CAF subtypes and, in turn, promotes CAF immunomodulatory properties and the formation of an immune-permissive tumor microenvironment (TME) by regulating ECM density [ 82 ].…”