Related Experiment Video
Updated: Mar 21, 2026
Development and Maintenance of a Preclinical Patient Derived Tumor Xenograft Model for the Investigation of Novel Anti-Cancer Therapies
Published on: September 30, 2016
CXCR2 blockade overcomes the NETosis-mediated resistance to MEK inhibition in pancreatic cancer models
Brian Herbst1,2,3,4,5, Alex B Blair1,3,5,6, Yiming Li1,3,4,7
1Department of Oncology and the Sidney Kimmel Comprehensive Cancer Center.
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.
Insights
Targeting KRAS-effectors with MEK inhibitors overcomes anti-PD-1 resistance in pancreatic cancer. Combining anti-PD-1, MEK, and CXCR2 inhibitors shows promise against immunosuppressive tumors.
Area of Science:
- Immunology
- Oncology
- Molecular Biology
Background:
- Pancreatic ductal adenocarcinoma (PDAC) is resistant to anti-PD-1 therapy due to an immunosuppressive tumor microenvironment (TME).
- KRAS mutations drive TME inflammation and resistance via MAPK signaling and IL-8 upregulation.
- Targeting downstream KRAS effectors is a potential strategy to enhance anti-PD-1 efficacy.
Purpose of the Study:
- To investigate MEK1/2 inhibition as a strategy to overcome anti-PD-1 resistance in PDAC.
- To explore the role of tumor-associated neutrophils (TANs) and IL-8/CXCR2 axis in therapeutic response.
- To develop a combination therapy overcoming resistance in Kras-mutated PDAC.
Main Methods:
- Utilized Krasmut KPC and KrasWT Panc02 mouse models.
- Administered anti-PD-1 antibody alone and in combination with MEK inhibitor (e.g., trametinib).
- Investigated downstream effects including TAN recruitment, CD8+ T cell infiltration, IFNgamma production, and NETosis.
Main Results:
- Combination of anti-PD-1 and MEK inhibitor showed antitumor activity in Krasmut KPC tumors, but not KrasWT Panc02 tumors.
- This combination induced TAN recruitment via CXCR2 and increased CD8+ T cells and IFNgamma in sensitive tumors.
- Further addition of anti-CXCR2 antibody overcame resistance in larger tumors by blocking TAN infiltration into hypoxic/necrotic areas.
- A risk score based on NETosis-MAPK signaling correlated with poorer survival in human PDAC.
Conclusions:
- MEK1/2 inhibition combined with anti-PD-1 antibody can overcome resistance in Kras-mutated PDAC.
- The IL-8/CXCR2 axis and TANs play a critical role in the response to this combination therapy.
- Targeting KRAS signaling, neutrophil infiltration, and PD-1 offers a promising therapeutic strategy for PDAC.
