Targeting TGF?R2-mutant tumors exposes vulnerabilities to stromal TGF? blockade in pancreatic cancer

TGF? is important during pancreatic ductal adenocarcinoma (PDA) progression. Canonical TGF? signaling suppresses epithelial pancreatic cancer cell proliferation; as a result inhibiting TGF? has not been successful in PDA. In contrast, we demonstrate that inhibition of stromal TGF?R2 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 TGF? signaling via loss of TGF?R2. We demonstrate that in PDA that harbors epithelial loss of TGF?R2, inhibition of TGF? signaling is selective for stromal cells and results in a therapeutic benefit. Our study highlights the potential benefit of TGF? blockade in PDA and the importance of stratifying PDA patients who might benefit from such therapy.