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J Exp Med

Title:		Interleukin-17-induced neutrophil extracellular traps mediate resistance to checkpoint blockade in pancreatic cancer
Author(s):		Zhang Y; Chandra V; Riquelme Sanchez E; Dutta P; Quesada PR; Rakoski A; Zoltan M; Arora N; Baydogan S; Horne W; Burks J; Xu H; Hussain P; Wang H; Gupta S; Maitra A; Bailey JM; Moghaddam SJ; Banerjee S; Sahin I; Bhattacharya P; McAllister F;
Address:		"Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, TX. Center for Integrative Biology, Faculty of Science, Universidad Mayor, Santiago, Chile. Cancer Systems Imaging, The University of Texas MD Anderson Cancer Center, Houston, TX. University of Minnesota, Minneapolis, MN. Richard King Mellon Foundation Institute for Pediatric Research, Children's Hospital of Pittsburgh, Pittsburgh, PA. Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX. Laboratory of Human Carcinogenesis, National Cancer Institute, Bethesda, MD. Department of Anatomical Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX. Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX. Sheikh Ahmed Center for Pancreatic Cancer Research, The University of Texas MD Anderson Cancer Center, Houston, TX. Department of Gastroenterology, University of Texas Health Sciences Center, Houston, TX. Pulmonary Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX. Department of Surgery, Sylvester Comprehensive Cancer Center, University of Miami Health System, Miami, FL. Department of Engineering, Texas Southern University, Houston, TX. Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX"
Journal Title:		J Exp Med
Year:		2020
Volume:		217
Issue:		12
Page Number:		-
DOI:		10.1084/jem.20190354
ISSN/ISBN:		1540-9538 (Electronic) 0022-1007 (Print) 0022-1007 (Linking)
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"
Keywords:		"Animals Biomarkers, Tumor/metabolism CD8-Positive T-Lymphocytes/drug effects/immunology Cell Line, Tumor Drug Resistance, Neoplasm/*drug effects Extracellular Traps/*metabolism Humans Immune Checkpoint Inhibitors/pharmacology/*therapeutic use Immunosuppre;"
Notes:		"MedlineZhang, 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 eng K12 CA088084/CA/NCI NIH HHS/ P30 CA016672/CA/NCI NIH HHS/ R37 CA237384/CA/NCI NIH HHS/ R50 CA243707/CA/NCI NIH HHS/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't 2020/08/30 J Exp Med. 2020 Dec 7; 217(12):e20190354. doi: 10.1084/jem.20190354"