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

Abstract

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.

Vasohibin‐2 plays an essential role in metastasis of pancreatic ductal adenocarcinoma

“…Increasing evidence indicates that MDSC not only provide evasion of tumor immunity but also augment the metastatic potential of tumor cells through promoting pre‐metastatic niche formation . Indeed, CXCR2 signaling is reported be responsible for the accumulation of MDSC in PDAC, and blockade of CXCR2 signaling contributes to improved tumor immunity and reduced metastasis of PDAC in mice . The transition of M1‐TAM to M2‐TAM is another aspect of immune response during the progression of PDAC, as the accumulation of M2‐TAM is evident in PDAC .…”

“…We noticed that VASH2 metastasis of PDAC in mice. 4,34 The transition of M1-TAM to M2-TAM is another aspect of immune response during the progression of PDAC, as the accumulation of M2-TAM is evident in PDAC. 30 The present study indicates that VASH2 is responsible for the modulation of tumor immunity through accumulation of M2-TAM as well.…”

Targeting the Tumor Microenvironment: An Unexplored Strategy for Mutant KRAS Tumors

“…In KRAS-driven PDAC mouse models, CAFs were shown to overexpress CXCR2 ligands promoting migration, invasion, and angiogenesis, and in fact, blocking the CXCLs-CXCR2 axis resulted in tumor cell apoptosis, decreased vessel density, and modulation of the immune infiltrate. Specifically, this led to reduced MPO+ neutrophils, CD11+ Ly6G+ MDSCs and arginase-1 (Arg-1)-positive macrophages (M2-like), as well as increased inducible nitric oxide synthase (iNOS)-positive macrophages (M1-like), with consequent improvement in mouse survival [90,91]. Moreover, other reports described that CAFs expressing FAP mediate immune suppression by secretion of CXCL12.…”

Chronic circadian disruption modulates breast cancer cell stemness and their immune microenvironment to drive metastasis in mice

“…Similarly to our findings, the CXCLs-CXCR2 axis have been implicated in the modulation of tumour immune microenvironment and enhanced metastatic invasion in mouse pancreatic cancer. 34,35 CXCR2 and several of its ligands (CXCL1, CXCL2, CXCL5, CXCL7 and CXCL8) have been linked to breast cancer progression and metastatic invasion. 83 It is important to note, that several of human and mouse chemokines are not direct homologues.…”

“…S8B, Table S3). As both CXCL12 and CXCL5 together with their respective receptors are described to be involved in metastatic processes [32][33][34][35] we also assessed the expression level of their receptors, respectively CXCR4 and CXCR2. We observed a significant increase in the number of CXCR4 + cancer cells ( Fig.…”