Abstract A58: TGF-beta inhibition and checkpoint blockade in mouse models for gastrointestinal cancer

Abstract Background: Gastrointestinal tumors are generally not responsive to checkpoint blockade unless they are hypermutated. Smad4 and p53 are frequently mutated in human gastrointestinal cancer. Methods: We conducted the intestinal epithelium-specific knockout of Smad4 and Trp53. Transcriptomic profiles were evaluated for spontaneous tumors that formed in these genetically engineered mice. Results: TGF-beta signaling pathway genes were overexpressed in bulk tumors formed in Villin-Cre;Smad4(F/F);Trp53(F/F). Efficacy of anti-PD-1 (10mg/kg IP BIW) and small-molecule ALK5 inhibitor (25mg/kg PO) was tested in syngeneic mice harboring heterotopic allografts of a cell line that was primarily cultured from a Smad4-null tumor. ALK5 inhibitor did not affect the growth of Smad4-null allograft as a monotherapy, but significantly enhanced the antiproliferative effect of anti-PD-1 as a combination treatment. Conclusion: TGF-beta pathway inhibition may be a promising approach to increase the efficacy of checkpoint blockade in gastrointestinal tumors. (NCC grants 1910021/1810951.) Citation Format: Kye S. Cho, Hark K. Kim. TGF-beta inhibition and checkpoint blockade in mouse models for gastrointestinal cancer [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2019 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(3 Suppl):Abstract nr A58.