Targeting TGF βR2‐mutant tumors exposes vulnerabilities to stromal TGF β blockade in pancreatic cancer

Abstract

TGFβ is important during pancreatic ductal adenocarcinoma (PDA) progression. Canonical TGFβ signaling suppresses epithelial pancreatic cancer cell proliferation; as a result, inhibiting TGFβ has not been successful in PDA. In contrast, we demonstrate that inhibition of stromal TGFβR2 reduces IL‐6 production from cancer‐associated fibroblasts, resulting in a reduction of STAT3 activation in tumor cells and reversion of the immunosuppressive landscape. Up to 7% of human PDA have tumor cell‐specific deficiency in canonical TGFβ signaling via loss of TGFβR2. We demonstrate that in PDA that harbors epithelial loss of TGFβR2, inhibition of TGFβ signaling is selective for stromal cells and results in a therapeutic benefit. Our study highlights the potential benefit of TGFβ blockade in PDA and the importance of stratifying PDA patients who might benefit from such therapy.

Toward personalized TGFβ inhibition for pancreatic cancer

“…Taken together, this extensive study from Huang et al illuminates key features of PDAC biology, challenges to treatment intervention, and the need for a more personalized approach. Over the course of PDAC development, a supportive niche is constructed composed of an extensive network of intercellular interactions with “normal” stromal and immune cells making up the TME.…”

“…The comparison of PDAC development to dysfunctional wound healing is especially striking given the key role of cytokine transforming growth factor beta (TGFβ) in both processes. In this issue of EMBO Molecular Medicine, Huang et al comprehensively and elegantly demonstrate a novel strategy by which TGFβ receptor 2 (TGFβR2) blockade in the stromal compartment can successfully treat PDAC tumors without intact TGFβ signaling. TGFβ effects are largely context dependent and have been shown to shape the phenotype of PDAC and its associated TME through a dual role (Massague, ; Ligorio et al , ).…”

“…However, the Brekken group previously demonstrated therapeutic efficacy of TGFβR2 inhibition using 2G8, a murine monoclonal antibody, in a PDAC patient‐derived xenograft model so as to selectively target the stroma (Ostapoff et al , ). Huang et al built upon these findings to elucidate the critical TGFβ‐driven PDAC TME signaling interactions.…”

“…In 3D culture, this CAF conditioned media resulted in rapid tumor growth and decreased E‐cadherin with increased N‐cadherin, markers of epithelial–mesenchymal transition (EMT). Thus, Huang et al defined a pro‐tumor TGFβ‐IL‐6 paracrine signaling axis between PDAC cancer cells and CAFs.…”

Cancer-Associated Fibroblasts: Versatile Players in the Tumor Microenvironment

“…In an in vitro melanoma model, CAFs produced MMPs, which resulted in the abrogation (through protein cleavage) of the activity of two cell surface proteins, MICA-A and MICA-B (MHC Class-I polypeptide-related sequence A/B), which are inducers of NK activation [141]. Furthermore, Huang et al demonstrated that TGF-β-induced secretion of IL-6 from CAFs inhibited NK cell activity in in vitro and in vivo murine PDAC models [142]. CAFs may also directly suppress NK cytotoxicity, as demonstrated by their ability to reduce NK secretion of perforins and granzymes as shown in an in vitro colorectal cancer model [143].…”