CXCR2 blockade overcomes the NETosis-mediated resistance to MEK inhibition in pancreatic cancer models

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. Thus, this study attempted to overcome the resistance to anti-PD-1 antibody by targeting downstream KRAS-effectors. The study found that the resistance to anti-PD-1 antibody can be overcome through MEK1/2-inhibition. The combination of anti-PD-1 antibody and MEK inhibitor displayed antitumor activity in Krasmut (mutated) KPC mouse tumors, but not KrasWT (wild-type) Panc02 tumors. The combination of anti-PD-1 antibody and MEK inhibitor induced recruitment of tumor-associated neutrophils (TANs) via CXCR2, an IL-8 receptor, and increased memory CD8+ T cells and IFNgamma production in treatment-sensitive tumors. However, larger tumors still resisted to the combination of anti-PD-1 antibody and MEK inhibitor likely due to hypoxia/necrosis-induced NETosis and associated paucity of CD8+ T cells. The subsequent addition of anti-CXCR2 antibody overcame this resistance by blocking TAN-infiltration to hypoxic/necrotic areas. Consistently, a risk-score based on the NETosis-MAPK signaling interaction is significantly associated with poorer survival in human PDACs. This study thus provides a new venue for overcoming resistance to strategies targeting KRAS signaling.