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Abstract
Single-agent anti-PD-1 antibodies are ineffective for pancreatic ductal adenocarcinoma (PDAC) due to the 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 antibodies by targeting downstream KRAS-effectors. The study found that the resistance to anti-PD-1 antibodies can be overcome through MEK1/2-inhibition. The combination of anti-PD-1 antibodies and MEK inhibitors displayed antitumor activity in Kras mutated (Krasmut) KPC mouse tumors, but not WT (KrasWT) Panc02 tumors. The combination of anti-PD-1 antibodies and MEK inhibitors induced recruitment of tumor-associated neutrophils (TANs) via CXCR2, an IL-8 receptor, and increased memory CD8+ T cells and IFN-γ production in treatment-sensitive tumors. However, larger tumors still resisted 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 PDAC. This study thus provides a new venue for overcoming resistance to strategies targeting KRAS signaling.
Authors
Brian Herbst, Alex Blair, Yiming Li, Elizabeth M. Jaffee, Lei Zheng
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Copyright © 2026 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)