Targeting TGFβR2-mutant tumors exposes vulnerabilities to stromal TGFβ blockade in pancreatic cancer.

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