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

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 designed peptides and was able to specifically bind to the pancreatic cancer cells as well as fibroblasts and macrophages and . 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.