Open AccessInterleukin-17–induced neutrophil extracellular traps mediate resistance to checkpoint blockade in pancreatic cancer
Author(s) -
Yu Zhang,
Vidhi Chandra,
Erick Riquelme Sanchez,
Prasanta Dutta,
Peter M. Quesada,
Amanda Rakoski,
Michelle Zoltan,
Nivedita Arora,
Seyda Baydogan,
William Horne,
Jared K. Burks,
Hanwen Xu,
Perwez Hussain,
Huamin Wang,
Sonal Gupta,
Anirban Maitra,
Jennifer M. Bailey,
Seyed Javad Moghaddam,
Sulagna Banerjee,
İsmet Şahin,
Pratip Bhattacharya,
Florencia McAllister
Publication year - 2020
Publication title -
the journal of experimental medicine/the journal of experimental medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 8.483
H-Index - 448
eISSN - 1540-9538
pISSN - 0022-1007
DOI - 10.1084/jem.20190354
Subject(s) - neutrophil extracellular traps , pancreatic cancer , cancer research , biology , immune checkpoint , interleukin 17 , tumor microenvironment , immunology , immune system , cancer , immunotherapy , inflammation , genetics
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.