Development of a CXCR4 antagonistic peptide, P12, to suppress pancreatic cancer progress via enhancing T cell responses and sensitizing cells to gemcitabine

Abstract

The C–X–C motif chemokine receptor 4 (CXCR4) is overexpressed by pancreatic cancer cells. This work developed a CXCR4 antagonistic peptide P12, which was identified by pancreatic-cell-based selection from among the de novo designed peptides and was able to specifically bind to the pancreatic cancer cells as well as fibroblasts and macrophages in vitro and in vivo. CXCL12-mediated migration of tumor cells and adhesion to stromal cells were effectively inhibited by P12, and the phosphorylation of Erk and P38 was down-regulated. P12 increased the sensitivity of the tumor cells and fibroblasts to gemcitabine (GEM). The combination of P12 with GEM (P12+GEM) increased the infiltration of CD8⁺ T cells and reduced fibroblasts in the tumor microenvironment, as well as increasing the toxicity of the lymphocytes to the tumor cells with upregulated blood levels of INF-γ and TNF-α. Collectively, P12+GEM decreased the tumor weight and prolonged the survival of tumor-bearing mice significantly. In conclusion, P12 is a potent and selective CXCR4 antagonist that effectively enhances anti-tumor immune responses and overcomes the gemcitabine resistance of pancreatic cancer.