Abstract PR07: Neutralizing the activity of murine TGF-β receptor 2 promotes a differentiated tumor cell phenotype and inhibits pancreatic cancer metastasis

Elevated levels of TGF-β are a negative prognostic indicator for patients diagnosed with pancreatic cancer; as a result the TGF-β pathway is an attractive target for therapy. However, clinical application of pharmacologic inhibition of TGF-β remains challenging because TGF-β has tumor suppressor functions in many epithelial malignancies including pancreatic cancer. In fact, direct neutralization of TGF-β promotes tumor progression of genetic murine models of pancreatic cancer. Here we report that neutralizing the activity of murine TGF-β receptor 2 using a monoclonal antibody (2G8) has potent anti-metastatic activity in orthotopic human tumor xenografts, syngenic tumors and a genetic model of pancreatic cancer. 2G8 induced an anti-metastatic stromal phenotype by increasing pro-inflammatory macrophages and NK cells and concomitantly decreasing anti-inflammatory macrophages, MDSCs and activated fibroblasts. These stromal specific changes resulted in tumor cell epithelial differentiation and a potent reduction in metastases. We conclude that TGF-β signaling within stromal cells participates directly in tumor cell phenotype and pancreatic cancer progression. Thus, strategies that inhibit TGF-β dependent effector functions of stromal cells could be efficacious for the therapy of pancreatic tumors. This abstract is also presented as Poster A38. Citation Format: Katherine T. Ostapoff, Bercin Kutluk Cenik, Miao Wang, Risheng Ye, Xiaohing Xu, Desiree Nugent, Michelle Hagopian, Mary Topalovski, Lee B. Rivera, Kyla D. Carroll, Rolf A. Brekken. Neutralizing the activity of murine TGF-β receptor 2 promotes a differentiated tumor cell phenotype and inhibits pancreatic cancer metastasis. [abstract]. In: Abstracts: AACR Special Conference on Cellular Heterogeneity in the Tumor Microenvironment; 2014 Feb 26-Mar 1; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(1 Suppl):Abstract nr PR07. doi:10.1158/1538-7445.CHTME14-PR07