Interleukin-17-induced neutrophil extracellular traps mediate resistance to checkpoint blockade in pancreatic cancer
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Updated: Dec 10, 2025
Flow Cytometry-Based Isolation and Therapeutic Evaluation of Tumor-Infiltrating Lymphocytes in a Mouse Model of Pancreatic Cancer
Published on: January 17, 2025
Yu Zhang1, Vidhi Chandra1, Erick Riquelme Sanchez1,2
1Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, TX.
Abstract:
Pancreatic ductal adenocarcinoma (PDAC) remains a lethal malignancy with an immunosuppressive microenvironment that is resistant to most therapies. IL17 is involved in pancreatic tumorigenesis, but its role in invasive PDAC is undetermined. We hypothesized that IL17 triggers and sustains PDAC immunosuppression. We inhibited IL17/IL17RA signaling using pharmacological and genetic strategies alongside mass cytometry and multiplex immunofluorescence techniques. We uncovered that IL17 recruits neutrophils, triggers neutrophil extracellular traps (NETs), and excludes cytotoxic CD8 T cells from tumors. Additionally, IL17 blockade increases immune checkpoint blockade (PD-1, CTLA4) sensitivity. Inhibition of neutrophils or Padi4-dependent NETosis phenocopies IL17 neutralization. NMR spectroscopy revealed changes in tumor lactate as a potential early biomarker for IL17/PD-1 combination efficacy. Higher expression of IL17 and PADI4 in human PDAC corresponds with poorer prognosis, and the serum of patients with PDAC has higher potential for NETosis. Clinical studies with IL17 and checkpoint blockade represent a novel combinatorial therapy with potential efficacy for this lethal disease.
Insights
Interleukin-17 (IL17) drives pancreatic cancer immunosuppression by recruiting neutrophils and hindering T cells. Blocking IL17 enhances immunotherapy, offering a novel treatment strategy for pancreatic ductal adenocarcinoma (PDAC).
Area of Science:
- Oncology
- Immunology
- Biochemistry
Background:
- Pancreatic ductal adenocarcinoma (PDAC) is a deadly cancer with an immunosuppressive tumor microenvironment, limiting treatment efficacy.
- The role of Interleukin-17 (IL17) in invasive PDAC and its contribution to immune evasion are not fully understood.
Purpose of the Study:
- To investigate the hypothesis that IL17 signaling promotes immunosuppression in PDAC.
- To explore the potential of targeting IL17/IL17RA signaling as a therapeutic strategy for PDAC.
Main Methods:
- Pharmacological and genetic inhibition of IL17/IL17RA signaling.
- Mass cytometry and multiplex immunofluorescence for immune cell profiling.
- NMR spectroscopy for metabolic analysis.
- Analysis of IL17 and PADI4 expression in human PDAC tissues and patient serum.
Main Results:
- IL17 recruits neutrophils, induces neutrophil extracellular traps (NETs), and excludes cytotoxic CD8 T cells from the tumor microenvironment.
- IL17 blockade enhances sensitivity to immune checkpoint inhibitors (PD-1, CTLA4).
- Inhibition of neutrophils or Padi4-dependent NETosis mimicked the effects of IL17 neutralization.
- Increased tumor lactate was observed, suggesting potential as a biomarker for combination therapy efficacy.
- Elevated IL17 and PADI4 expression correlate with poorer prognosis in human PDAC patients.
Conclusions:
- IL17 plays a critical role in PDAC immunosuppression by promoting neutrophil recruitment, NETosis, and CD8 T cell exclusion.
- Targeting IL17 signaling, in combination with immune checkpoint blockade, represents a promising therapeutic approach for PDAC.
- NETosis potential in patient serum and tumor lactate levels may serve as predictive biomarkers for treatment response.
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