Interleukin-17–induced neutrophil extracellular traps mediate resistance to checkpoint blockade in pancreatic cancer

• Published in: The Journal of experimental medicine Vol. 217; no. 12
• Main Authors: Zhang, Yu, Chandra, Vidhi, Riquelme Sanchez, Erick, Dutta, Prasanta, Quesada, Pompeyo R., Rakoski, Amanda, Zoltan, Michelle, Arora, Nivedita, Baydogan, Seyda, Horne, William, Burks, Jared, Xu, Hanwen, Hussain, Perwez, Wang, Huamin, Gupta, Sonal, Maitra, Anirban, Bailey, Jennifer M., Moghaddam, Seyed J., Banerjee, Sulagna, Sahin, Ismet, Bhattacharya, Pratip, McAllister, Florencia
• Format: Journal Article
• Language: English
• Published: United States Rockefeller University Press 07.12.2020
• Subjects: Animals; Biomarkers, Tumor - metabolism; CD8-Positive T-Lymphocytes - drug effects; CD8-Positive T-Lymphocytes - immunology; Cell Line, Tumor; Drug Resistance, Neoplasm - drug effects; Extracellular Traps - metabolism; Humans; Immune Checkpoint Inhibitors - pharmacology; Immune Checkpoint Inhibitors - therapeutic use; Immunosuppression; Innate immunity and inflammation; Interleukin-17 - pharmacology; Lymphocyte Activation - drug effects; Mice, Inbred C57BL; Neutrophils - drug effects; Neutrophils - pathology; Pancreatic Neoplasms - drug therapy; Pancreatic Neoplasms - immunology; Pancreatic Neoplasms - pathology; Programmed Cell Death 1 Receptor - metabolism; Signal Transduction - drug effects; Solid Tumors; Tumor immunology; Tumor Microenvironment - drug effects
• ISSN: 0022-1007; 1540-9538; 1540-9538
• DOI: 10.1084/jem.20190354

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.