Targeting TGFßR2-mutant tumors exposes vulnerabilities to stromal TGFß blockade in pancreatic cancer.

ABSTRACT

TGFß is important during pancreatic ductal adenocarcinoma (PDA) progression. Canonical TGFß signaling suppresses epithelial pancreatic cancer cell proliferation; as a result, inhibiting TGFß has not been successful in PDA. In contrast, we demonstrate that inhibition of stromal TGFßR2 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 TGFß signaling via loss of TGFßR2. We demonstrate that in PDA that harbors epithelial loss of TGFßR2, inhibition of TGFß signaling is selective for stromal cells and results in a therapeutic benefit. Our study highlights the potential benefit of TGFß blockade in PDA and the importance of stratifying PDA patients who might benefit from such therapy.