Interleukin-17–induced neutrophil extracellular traps mediate resistance to checkpoint blockade in pancreatic cancer-Reference-Cited by-同舟云学术

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

Published:2020-08-28 Issue:12 Volume:217 Page:
ISSN:0022-1007
Container-title:Journal of Experimental Medicine
language:en
Short-container-title:

Author:

Zhang Yu¹,Chandra Vidhi¹^ORCID,Riquelme Sanchez Erick¹²^ORCID,Dutta Prasanta³,Quesada Pompeyo R.¹^ORCID,Rakoski Amanda¹^ORCID,Zoltan Michelle¹^ORCID,Arora Nivedita⁴^ORCID,Baydogan Seyda¹^ORCID,Horne William⁵,Burks Jared⁶^ORCID,Xu Hanwen¹^ORCID,Hussain Perwez⁷,Wang Huamin⁸⁹,Gupta Sonal⁸^ORCID,Maitra Anirban⁸⁹¹⁰^ORCID,Bailey Jennifer M.¹¹^ORCID,Moghaddam Seyed J.¹²^ORCID,Banerjee Sulagna¹³^ORCID,Sahin Ismet¹⁴^ORCID,Bhattacharya Pratip³,McAllister Florencia¹¹⁵^ORCID

Affiliation:

1. Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, TX

2. Center for Integrative Biology, Faculty of Science, Universidad Mayor, Santiago, Chile

3. Cancer Systems Imaging, The University of Texas MD Anderson Cancer Center, Houston, TX

4. University of Minnesota, Minneapolis, MN

5. Richard King Mellon Foundation Institute for Pediatric Research, Children’s Hospital of Pittsburgh, Pittsburgh, PA

6. Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX

7. Laboratory of Human Carcinogenesis, National Cancer Institute, Bethesda, MD

8. Department of Anatomical Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX

9. Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX

10. Sheikh Ahmed Center for Pancreatic Cancer Research, The University of Texas MD Anderson Cancer Center, Houston, TX

11. Department of Gastroenterology, University of Texas Health Sciences Center, Houston, TX

12. Pulmonary Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX

13. Department of Surgery, Sylvester Comprehensive Cancer Center, University of Miami Health System, Miami, FL

14. Department of Engineering, Texas Southern University, Houston, TX

15. Gastrointestinal Medical Oncology, 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.

Funder

Pancreatic Cancer Action Network

American Association for Cancer Research

National Pancreas Foundation

V Foundation for Cancer Research

Paul Calabresi K12

National Cancer Institute

Andrew Sabin Family Foundation

Stand Up to Cancer

The University of Texas MD Anderson Cancer Center

AGA Research Foundation

Publisher