TY - JOUR
T1 - Interleukin-17-induced neutrophil extracellular traps mediate resistance to checkpoint blockade in pancreatic cancer
AU - Zhang, Yu
AU - Chandra, Vidhi
AU - Sanchez, Erick Riquelme
AU - Dutta, Prasanta
AU - Quesada, Pompeyo R.
AU - Rakoski, Amanda
AU - Zoltan, Michelle
AU - Arora, Nivedita
AU - Baydogan, Seyda
AU - Horne, William
AU - Burks, Jared
AU - Xu, Hanwen
AU - Hussain, Perwez
AU - Wang, Huamin
AU - Gupta, Sonal
AU - Maitra, Anirban
AU - Bailey, Jennifer M.
AU - Moghaddam, Seyed J.
AU - Banerjee, Sulagna
AU - Sahin, Ismet
AU - Bhattacharya, Pratip
AU - McAllister, Florencia
N1 - Publisher Copyright:
© 2020 Zhang et al. This article is distributed under the terms of an Attribution-Noncommercial-Share Alike-No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms/). After six months it is available under a Creative Commons License (Attribution-Noncommercial-Share Alike 4.0 International license, as described at https://creativecommons.org/licenses/by-nc-sa/4.0/).
PY - 2020/12/7
Y1 - 2020/12/7
N2 - 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.
AB - 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.
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U2 - 10.1084/jem.20190354
DO - 10.1084/jem.20190354
M3 - Article
C2 - 32860704
AN - SCOPUS:85090170903
SN - 0022-1007
VL - 217
JO - Journal of Experimental Medicine
JF - Journal of Experimental Medicine
IS - 12
M1 - e20190354
ER -