Blocking CXCLs–CXCR2 axis in tumor–stromal interactions contributes to survival in a mouse model of pancreatic ductal adenocarcinoma through reduced cell invasion/migration and a shift of immune-inflammatory microenvironment

Pancreatic ductal adenocarcinoma (PDAC) is characterized by dense stromal reaction (desmoplasia). We have previously reported that mice with conditional Kras(G12D) mutation and knockout of TGF-β receptor type II (Tgfbr2), PKF mice, develop PDAC with desmoplasia modulated by CXC chemokines that are produced by PDAC cells through tumor–stromal interaction. In this study, we further discovered that PDAC and cancer-associated fibroblast (CAF) accelerated each other’s invasion and migration through the CXC chemokines-receptor (CXCLs–CXCR2) axis. Heterozygous knockout of Cxcr2 in PKF mice (PKF2h mice) prolonged survival and inhibited both tumor angiogenesis and PDAC microinvasion. Infiltration of neutrophils, myeloid-derived suppressor cells (MDSCs), and arginase-1(+) M2-like tumor-associated macrophages (TAMs) significantly decreased in the tumors of PKF2h mice, whereas inducible nitric oxide synthase (iNOS)(+) M1-like TAMs and apoptotic tumor cells markedly increased, which indicated that blockade of the CXCLs–CXCR2 axis resulted in a shift of immune-inflammatory microenvironment. These results suggest that blocking of the CXCLs–CXCR2 axis in tumor–stromal interactions could be a therapeutic approach against PDAC progression.