{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T13:17:58Z","timestamp":1789391878175,"version":"build-2803163510"},"reference-count":44,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,10,17]],"date-time":"2022-10-17T00:00:00Z","timestamp":1665964800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100019018","name":"Chinese Academy of Medical Sciences Initiative for Innovative Medicine","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100019018","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>Extracellular traps (ETs) and tumor-infiltrating immune cells play crucial roles in tumor progression. However, little is known about the clinical significance of tumor-infiltrating neutrophils and macrophages and the related ETs in pancreatic ductal adenocarcinoma (PDAC). This study investigates the associations between neutrophil or macrophage infiltration or ET formation and the clinicopathological features, molecular characteristics, immune checkpoint molecules, clinical outcomes, and response to adjuvant chemotherapy (ACT) in PDAC. We performed multiplex immunofluorescence staining to detect ET formation by neutrophils or macrophages using tissue microarrays obtained from 205 patients, and analyzed the immunohistochemistry data for PD-L1, PD-L2, B7-H3, and B7-H4. The ET expression rates in macrophages and neutrophils were 23.9% and 45.4%, respectively. Patients with a high density of neutrophils or positive expression of neutrophil ETs exhibited poorer progression-free survival (PFS) and disease-specific survival (DSS), whereas macrophage ETs were not related to PFS and DSS. Neutrophil infiltration and ET formation were identified as independent prognostic predictors of DSS using univariate and multivariate Cox analyses. Patients with PDAC with lower neutrophil infiltration or negative staining for neutrophil ETs are more likely to benefit from ACT. Patients with PDAC were more accurately stratified based on the infiltration of neutrophils and presence of neutrophil ETs, and patients with low neutrophil infiltration and negative staining for neutrophil ETs showed the best survival. Patients with positive neutrophil ETs demonstrated inferior DSS compared to those with negative neutrophil ETs in the PD-L1 tumor proportion score (TPS) &amp;lt; 1% and PD-L1 IC &amp;lt; 1% subgroups. However, the positive expression of neutrophil ETs was not related to DSS in the PD-L1 TPS \u2265 1% or PD-L1 IC \u2265 1% subgroup. Our findings emphasize the potential of neutrophil infiltration and ETs as prognostic markers that could guide the formulation of more effective personalized treatments for PDAC.<\/jats:p>","DOI":"10.3389\/fimmu.2022.1027459","type":"journal-article","created":{"date-parts":[[2022,10,17]],"date-time":"2022-10-17T05:44:10Z","timestamp":1665985450000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":19,"title":["Intratumoral neutrophil extracellular traps are associated with unfavorable clinical outcomes and immunogenic context in pancreatic ductal adenocarcinoma"],"prefix":"10.3389","volume":"13","author":[{"given":"Xianlong","family":"Chen","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heng","family":"Ma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shengwei","family":"Mo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuangni","family":"Yu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhaohui","family":"Lu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jie","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,10,17]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(10)62307-0","article-title":"Pancreatic cancer","volume":"378","author":"Vincent","year":"2011","journal-title":"Lancet"},{"key":"B2","doi-asserted-by":"publisher","first-page":"7","DOI":"10.3322\/caac.21654","article-title":"Cancer statistics, 2021","volume":"71","author":"Siegel","year":"2021","journal-title":"CA Cancer J Clin"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1038\/nrgastro.2015.215","article-title":"Pancreatic cancer in 2015: Precision medicine in pancreatic cancer\u2013fact or fiction","volume":"13","author":"Seufferlein","year":"2016","journal-title":"Nat Rev Gastroenterol Hepatol"},{"key":"B4","doi-asserted-by":"publisher","first-page":"1625","DOI":"10.1053\/j.gastro.2018.08.009","article-title":"Immune cell and stromal signature associated with progression-free survival of patients with resected pancreatic ductal adenocarcinoma","volume":"155","author":"Mahajan","year":"2018","journal-title":"Gastroenterology"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccr.2014.04.021","article-title":"Stromal elements act to restrain, rather than support, pancreatic ductal adenocarcinoma","volume":"25","author":"Rhim","year":"2014","journal-title":"Cancer Cell"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1126\/science.aax0182","article-title":"Neoadjuvant checkpoint blockade for cancer immunotherapy","volume":"367","author":"Topalian","year":"2020","journal-title":"Science"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1126\/sciimmunol.aay6017","article-title":"Defining the emergence of myeloid-derived suppressor cells in breast cancer using single-cell transcriptomics","volume":"5","author":"Alshetaiwi","year":"2020","journal-title":"Sci Immunol"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1111\/imr.12444","article-title":"Neutrophils in cancer","volume":"273","author":"Treffers","year":"2016","journal-title":"Immunol Rev"},{"key":"B9","doi-asserted-by":"publisher","first-page":"15","DOI":"10.32607\/actanaturae.11503","article-title":"Neutrophil extracellular traps (NETs): Opportunities for targeted therapy","volume":"13","author":"Volkov","year":"2021","journal-title":"Acta Naturae"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1038\/nri.2017.105","article-title":"Neutrophil extracellular traps in immunity and disease","volume":"18","author":"Papayannopoulos","year":"2018","journal-title":"Nat Rev Immunol"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1038\/nm.4462","article-title":"Macrophage extracellular trap formation promoted by platelet activation is a key mediator of rhabdomyolysis-induced acute kidney injury","volume":"24","author":"Okubo","year":"2018","journal-title":"Nat Med"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2021.577517","article-title":"Neutrophil extracellular traps and macrophage extracellular traps predict postoperative recurrence in resectable nonfunctional pancreatic neuroendocrine tumors","volume":"12","author":"Xu","year":"2021","journal-title":"Front Immunol"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2013.00048","article-title":"A proposed role for neutrophil extracellular traps in cancer immunoediting","volume":"4","author":"Berger-Achituv","year":"2013","journal-title":"Front Immunol"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1002\/hep.29914","article-title":"Neutrophil extracellular traps promote inflammation and development of hepatocellular carcinoma in nonalcoholic steatohepatitis","volume":"68","author":"van der Windt","year":"2018","journal-title":"Hepatology"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2021.785222","article-title":"Neutrophil extracellular traps promote T cell exhaustion in the tumor microenvironment","volume":"12","author":"Kaltenmeier","year":"2021","journal-title":"Front Immunol"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.3390\/cancers13215333","article-title":"Neutrophils extracellular traps inhibition improves PD-1 blockade immunotherapy in colorectal cancer","volume":"13","author":"Zhang","year":"2021","journal-title":"Cancers (Basel)"},{"key":"B17","doi-asserted-by":"publisher","first-page":"91","DOI":"10.1016\/j.semcancer.2021.07.011","article-title":"Neutrophil extracellular traps in cancer","volume":"79","author":"Cristinziano","year":"2022","journal-title":"Semin Cancer Biol"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1038\/srep08008","article-title":"Capsular polysaccharides from cryptococcus neoformans modulate production of neutrophil extracellular traps (NETs) by human neutrophils","volume":"5","author":"Rocha","year":"2015","journal-title":"Sci Rep"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1111\/pim.12821","article-title":"Neutrophils from patients with the cardiac clinical form of chagas disease release less NETs than neutrophils from healthy individuals","volume":"43","author":"Duarte de Almeida","year":"2021","journal-title":"Parasite Immunol"},{"key":"B20","doi-asserted-by":"publisher","first-page":"19630","DOI":"10.1038\/s41598-020-76781-0","article-title":"The emerging role of neutrophil extracellular traps in severe acute respiratory syndrome coronavirus 2 (COVID-19)","volume":"10","author":"Arcanjo","year":"2020","journal-title":"Sci Rep"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1038\/s41385-018-0045-0","article-title":"Neutrophil extracellular traps prevent HIV infection in the female genital tract","volume":"11","author":"Barr","year":"2018","journal-title":"Mucosal Immunol"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pntd.0007368","article-title":"Neutrophil extracellular traps contribute to the pathogeny of leprosy type 2 reactions","volume":"13","author":"da Silva","year":"2019","journal-title":"PloS Negl Trop Dis"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1016\/j.chom.2010.10.005","article-title":"Statins enhance formation of phagocyte extracellular traps","volume":"8","author":"Chow","year":"2010","journal-title":"Cell Host Microbe"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1016\/j.jtho.2021.04.016","article-title":"Intratumoral CD39(+)CD8(+) T cells predict response to programmed cell death protein-1 or programmed death ligand-1 blockade in patients with NSCLC","volume":"16","author":"Yeong","year":"2021","journal-title":"J Thorac Oncol"},{"key":"B25","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1159\/000480373","article-title":"Macrophage extracellular traps: A scoping review","volume":"10","author":"Doster","year":"2018","journal-title":"J Innate Immun"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1002\/path.5212","article-title":"Extracellular traps derived from macrophages, mast cells, eosinophils and neutrophils are generated in a time-dependent manner during atherothrombosis","volume":"247","author":"Pertiwi","year":"2019","journal-title":"J Pathol"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1158\/2326-6066.CIR-18-0822","article-title":"Programmed cell death ligand-1 (PD-L1) and CD8 expression profiling identify an immunologic subtype of pancreatic ductal adenocarcinomas with favorable survival","volume":"7","author":"Danilova","year":"2019","journal-title":"Cancer Immunol Res"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1038\/modpathol.2015.89","article-title":"Mismatch repair status may predict response to adjuvant chemotherapy in resectable pancreatic ductal adenocarcinoma","volume":"28","author":"Riazy","year":"2015","journal-title":"Mod Pathol"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1002\/cjp2.259","article-title":"PD-L1 and PD-L2 expression in pancreatic ductal adenocarcinoma and their correlation with immune infiltrates and DNA damage response molecules","volume":"8","author":"Zhang","year":"2022","journal-title":"J Pathol Clin Res"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1002\/cjp2.260","article-title":"Analysis of a novel immune checkpoint, siglec-15, in pancreatic ductal adenocarcinoma","volume":"8","author":"Chen","year":"2022","journal-title":"J Pathol Clin Res"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.5858\/arpa.2021-0471-OA","article-title":"Prognostic value of programmed death ligand-1 in discriminating patients with lymph node-negative, p53-Wild-Type, or low-BRCA1\/2-Expression pancreatic ductal adenocarcinoma","author":"Chen","year":"2022","journal-title":"Arch Pathol Lab Med"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2020.01749","article-title":"The emerging role of neutrophil extracellular traps (NETs) in tumor progression and metastasis","volume":"11","author":"Masucci","year":"2020","journal-title":"Front Immunol"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1155\/2017\/4915062","article-title":"Neutrophil extracellular trap production in patients with colorectal cancer in vitro","volume":"2017","author":"Richardson","year":"2017","journal-title":"Int J Inflam"},{"key":"B34","doi-asserted-by":"publisher","first-page":"361ra138","DOI":"10.1126\/scitranslmed.aag1711","article-title":"Cancer cells induce metastasis-supporting neutrophil extracellular DNA traps","volume":"8","author":"Park","year":"2016","journal-title":"Sci Transl Med"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-15-1591","article-title":"Neutrophil extracellular traps promote the development and progression of liver metastases after surgical stress","volume":"76","author":"Tohme","year":"2016","journal-title":"Cancer Res"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-14-3299","article-title":"Neutrophil extracellular traps accumulate in peripheral blood vessels and compromise organ function in tumor-bearing animals","volume":"75","author":"Cedervall","year":"2015","journal-title":"Cancer Res"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-19-0800","article-title":"Neutrophil extracellular traps drive mitochondrial homeostasis in tumors to augment growth","volume":"79","author":"Yazdani","year":"2019","journal-title":"Cancer Res"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1002\/bjs.10187","article-title":"Infiltrating immune cells and gene mutations in pancreatic ductal adenocarcinoma","volume":"103","author":"Wang","year":"2016","journal-title":"Br J Surg"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-16-0617","article-title":"Interleukin-17-Producing neutrophils link inflammatory stimuli to disease progression by promoting angiogenesis in gastric cancer","volume":"23","author":"Li","year":"2017","journal-title":"Clin Cancer Res"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.15252\/emmm.201910681","article-title":"Neutrophils suppress tumor-infiltrating T cells in colon cancer via matrix metalloproteinase-mediated activation of TGF\u03b2","volume":"12","author":"Germann","year":"2020","journal-title":"EMBO Mol Med"},{"key":"B41","doi-asserted-by":"publisher","first-page":"1646","DOI":"10.1053\/j.gastro.2016.02.040","article-title":"Tumor-associated neutrophils recruit macrophages and T-regulatory cells to promote progression of hepatocellular carcinoma and resistance to sorafenib","volume":"150","author":"Zhou","year":"2016","journal-title":"Gastroenterology"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-17-0162","article-title":"Stratification of pancreatic ductal adenocarcinoma: Combinatorial genetic, stromal, and immunologic markers","volume":"23","author":"Knudsen","year":"2017","journal-title":"Clin Cancer Res"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMra1703413","article-title":"Precision diagnosis and treatment for advanced non-Small-Cell lung cancer","volume":"377","author":"Reck","year":"2017","journal-title":"N Engl J Med"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1016\/j.cellimm.2019.104008","article-title":"B7-H4, a promising target for immunotherapy","volume":"347","author":"Wang","year":"2020","journal-title":"Cell Immunol"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2022.1027459\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,10,17]],"date-time":"2022-10-17T05:44:14Z","timestamp":1665985454000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2022.1027459\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,10,17]]},"references-count":44,"alternative-id":["10.3389\/fimmu.2022.1027459"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2022.1027459","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,10,17]]},"article-number":"1027459"}}