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

Yu Zhang(The University of Texas MD Anderson Cancer Center), Vidhi Chandra(The University of Texas MD Anderson Cancer Center), Erick Riquelme(Universidad Mayor), Prasanta Dutta(The University of Texas MD Anderson Cancer Center), P Quesada(The University of Texas MD Anderson Cancer Center), Amanda Rakoski(The University of Texas MD Anderson Cancer Center), Michelle Zoltan(The University of Texas MD Anderson Cancer Center), Nivedita Arora(University of Minnesota), Seyda Baydogan(The University of Texas MD Anderson Cancer Center), William Horne(Children's Hospital of Pittsburgh), Jared K. Burks(The University of Texas MD Anderson Cancer Center), Hanwen Xu(The University of Texas MD Anderson Cancer Center), S. Perwez Hussain(National Cancer Institute), Huamin Wang(The University of Texas MD Anderson Cancer Center), Sonal Gupta(The University of Texas MD Anderson Cancer Center), Anirban Maitra(The University of Texas MD Anderson Cancer Center), Jennifer M. Bailey(The University of Texas Health Science Center at Houston), Seyed Javad Moghaddam(The University of Texas MD Anderson Cancer Center), Sulagna Banerjee(University of Miami Health System), İsmet Şahin(Texas Southern University), Pratip K. Bhattacharya(The University of Texas MD Anderson Cancer Center), Florencia McAllister(The University of Texas MD Anderson Cancer Center)
The Journal of Experimental Medicine
August 28, 2020
10.1084/jem.20190354
Cited by 446Open Access
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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.

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