CXCR2 blockade overcomes the NETosis-mediated resistance to MEK inhibition in pancreatic cancer models
Brian Herbst, Alex Blair, Yiming Li, Elizabeth M. Jaffee, Lei Zheng
Brian Herbst, Alex Blair, Yiming Li, Elizabeth M. Jaffee, Lei Zheng
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Research Article Immunology Oncology

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

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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Figure 1

Inhibition of MEK1/2 signaling overcomes the resistance to anti-PD-1 blockade and, in combination with anti-PD-1 blockade, increases overall survival in the orthotopic KPC mouse model of PDAC.

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Inhibition of MEK1/2 signaling overcomes the resistance to anti-PD-1 blo...
(A) Treatment schema of the orthotopic KPC mouse model with aPD-1 and KRAS effector inhibitors. The KPC001 cell line was used. Tumors were measured via ultrasound on days 0, 7, and 14 in B and weekly until Week 9 in D. (B) Representative tumor growth curves of aPD-1 combined with inhibition of KRAS effectors and associated pathways. n = 5 per group. (C) Kaplan-Meier survival curves of treatment groups in B. (D) Tumor growth curves of mice treated with aPD-1 ± MEKi in one representative experiment. n = 5 per group. Note that mice in the aPD-1 + DMSO group all met the survival endpoints, which were defined by morbidities instead of tumor size for the orthotopic model, and thus were euthanized by Day 32. (E) Kaplan-Meier survival curves of mice in D. Results are shown as mean ± SEM. Mixed effects model was used to compare tumor growth curves with Tukey’s corrections. For survival curves, Log-rank tests were performed followed by pairwise comparisons with Benjamin-Hochberg corrections. Key treatment groups were repeated at least twice. DMSO, vehicle; MEKi, MEK inhibitor; PI3Ki, PI3K inhibitor; RALi, RAL inhibitor; SHHi, Sonic hedgehog inhibitor; aPD-1, anti-PD-1 antibody; IgG, isotype control IgG for aPD-1. *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001.