CXCR2 blockade overcomes the NETosis-mediated resistance to MEK inhibition in pancreatic cancer models - PubMed
5 hours ago
- #Pancreatic Cancer
- #NETosis
- #Immunotherapy
- Single-agent anti-PD-1 antibody is ineffective for pancreatic ductal adenocarcinoma (PDAC) due to its immunosuppressive tumor-microenvironment (TME).
- KRAS-mutations contribute to the inflammatory TME and therapeutic resistance by upregulating IL-8 via MAPK pathways.
- Combination of anti-PD-1 antibody and MEK inhibitor showed antitumor activity in Krasmut KPC mouse tumors but not in KrasWT Panc02 tumors.
- The combination therapy induced recruitment of tumor-associated neutrophils (TANs) via CXCR2 and increased memory CD8+ T cells and IFNgamma production.
- Larger tumors resisted the combination therapy due to hypoxia/necrosis-induced NETosis and associated lack of CD8+ T cells.
- Addition of anti-CXCR2 antibody overcame resistance by blocking TAN-infiltration to hypoxic/necrotic areas.
- A risk-score based on NETosis-MAPK signaling interaction is associated with poorer survival in human PDACs.