Interleukin-17-induced neutrophil extracellular traps mediate resistance to checkpoint blockade in pancreatic cancer
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 immuno...
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| Veröffentlicht in: | The Journal of experimental medicine 2020-12, Vol.217 (12) |
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| creator | Zhang, 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 |
| description | 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. |
| doi_str_mv | 10.1084/jem.20190354 |
| format | Article |
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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.</description><identifier>ISSN: 0022-1007</identifier><identifier>EISSN: 1540-9538</identifier><identifier>DOI: 10.1084/jem.20190354</identifier><identifier>PMID: 32860704</identifier><language>eng</language><publisher>United States: Rockefeller University Press</publisher><subject>Animals ; Biomarkers, Tumor - metabolism ; CD8-Positive T-Lymphocytes - drug effects ; CD8-Positive T-Lymphocytes - immunology ; Cell Line, Tumor ; Drug Resistance, Neoplasm - drug effects ; Extracellular Traps - metabolism ; Humans ; Immune Checkpoint Inhibitors - pharmacology ; Immune Checkpoint Inhibitors - therapeutic use ; Immunosuppression ; Innate immunity and inflammation ; Interleukin-17 - pharmacology ; Lymphocyte Activation - drug effects ; Mice, Inbred C57BL ; Neutrophils - drug effects ; Neutrophils - pathology ; Pancreatic Neoplasms - drug therapy ; Pancreatic Neoplasms - immunology ; Pancreatic Neoplasms - pathology ; Programmed Cell Death 1 Receptor - metabolism ; Signal Transduction - drug effects ; Solid Tumors ; Tumor immunology ; Tumor Microenvironment - drug effects</subject><ispartof>The Journal of experimental medicine, 2020-12, Vol.217 (12)</ispartof><rights>2020 Zhang et al.</rights><rights>2020 Zhang et al. 2020</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c450t-6959217401bcc126192317117e913e8bbb82bdb1e97d3976d7482f426da1bce43</citedby><cites>FETCH-LOGICAL-c450t-6959217401bcc126192317117e913e8bbb82bdb1e97d3976d7482f426da1bce43</cites><orcidid>0000-0003-3642-2144 ; 0000-0003-0594-5102 ; 0000-0002-2696-7995 ; 0000-0003-2338-1662 ; 0000-0002-9455-640X ; 0000-0002-6173-9074 ; 0000-0002-0855-7124 ; 0000-0002-1081-8231 ; 0000-0001-7923-9978 ; 0000-0003-4865-7071 ; 0000-0002-9915-0943 ; 0000-0002-8762-577X ; 0000-0002-4750-106X ; 0000-0002-5350-307X ; 0000-0003-3630-6696 ; 0000-0002-5393-5606</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,780,784,885,27922,27923</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/32860704$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Zhang, Yu</creatorcontrib><creatorcontrib>Chandra, Vidhi</creatorcontrib><creatorcontrib>Riquelme Sanchez, Erick</creatorcontrib><creatorcontrib>Dutta, Prasanta</creatorcontrib><creatorcontrib>Quesada, Pompeyo R</creatorcontrib><creatorcontrib>Rakoski, Amanda</creatorcontrib><creatorcontrib>Zoltan, Michelle</creatorcontrib><creatorcontrib>Arora, Nivedita</creatorcontrib><creatorcontrib>Baydogan, Seyda</creatorcontrib><creatorcontrib>Horne, William</creatorcontrib><creatorcontrib>Burks, Jared</creatorcontrib><creatorcontrib>Xu, Hanwen</creatorcontrib><creatorcontrib>Hussain, Perwez</creatorcontrib><creatorcontrib>Wang, Huamin</creatorcontrib><creatorcontrib>Gupta, Sonal</creatorcontrib><creatorcontrib>Maitra, Anirban</creatorcontrib><creatorcontrib>Bailey, Jennifer M</creatorcontrib><creatorcontrib>Moghaddam, Seyed J</creatorcontrib><creatorcontrib>Banerjee, Sulagna</creatorcontrib><creatorcontrib>Sahin, Ismet</creatorcontrib><creatorcontrib>Bhattacharya, Pratip</creatorcontrib><creatorcontrib>McAllister, Florencia</creatorcontrib><title>Interleukin-17-induced neutrophil extracellular traps mediate resistance to checkpoint blockade in pancreatic cancer</title><title>The Journal of experimental medicine</title><addtitle>J Exp Med</addtitle><description>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.</description><subject>Animals</subject><subject>Biomarkers, Tumor - metabolism</subject><subject>CD8-Positive T-Lymphocytes - drug effects</subject><subject>CD8-Positive T-Lymphocytes - immunology</subject><subject>Cell Line, Tumor</subject><subject>Drug Resistance, Neoplasm - drug effects</subject><subject>Extracellular Traps - metabolism</subject><subject>Humans</subject><subject>Immune Checkpoint Inhibitors - pharmacology</subject><subject>Immune Checkpoint Inhibitors - therapeutic use</subject><subject>Immunosuppression</subject><subject>Innate immunity and inflammation</subject><subject>Interleukin-17 - pharmacology</subject><subject>Lymphocyte Activation - drug effects</subject><subject>Mice, Inbred C57BL</subject><subject>Neutrophils - drug effects</subject><subject>Neutrophils - pathology</subject><subject>Pancreatic Neoplasms - drug therapy</subject><subject>Pancreatic Neoplasms - immunology</subject><subject>Pancreatic Neoplasms - pathology</subject><subject>Programmed Cell Death 1 Receptor - metabolism</subject><subject>Signal Transduction - drug effects</subject><subject>Solid Tumors</subject><subject>Tumor immunology</subject><subject>Tumor Microenvironment - drug effects</subject><issn>0022-1007</issn><issn>1540-9538</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2020</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpVkM1OwzAQhC0EoqVw44z8AAS8thPHFyRU8VMJiQucI8fZUtPUiRwHwdvjqlDBaVfamdnRR8g5sCtgpbx-x80VZ6CZyOUBmUIuWaZzUR6SKWOcZ8CYmpCTYXhnDKTMi2MyEbwsmGJySuLCRwwtjmvnM1CZ881osaEexxi6fuVaip8xGIttO7Ym0LT3A91g40xEGnBwQzTeIo0dtSu0675zPtK67ezaNEidp326BzTRWWq30nBKjpamHfDsZ87I6_3dy_wxe3p-WMxvnzIrcxazQueag5IMamuBF6C5AAWgUIPAsq7rktdNDahVI7QqGiVLvpS8aExyoBQzcrPL7cc6NbboU_u26oPbmPBVdcZV_y_eraq37qNSCaASOgVc7gJs6IYh4HLvBVZt6VeJfvVLP8kv_v7bi39xi2-KM4Ox</recordid><startdate>20201207</startdate><enddate>20201207</enddate><creator>Zhang, Yu</creator><creator>Chandra, Vidhi</creator><creator>Riquelme Sanchez, Erick</creator><creator>Dutta, Prasanta</creator><creator>Quesada, Pompeyo R</creator><creator>Rakoski, Amanda</creator><creator>Zoltan, Michelle</creator><creator>Arora, Nivedita</creator><creator>Baydogan, Seyda</creator><creator>Horne, William</creator><creator>Burks, Jared</creator><creator>Xu, Hanwen</creator><creator>Hussain, Perwez</creator><creator>Wang, Huamin</creator><creator>Gupta, Sonal</creator><creator>Maitra, Anirban</creator><creator>Bailey, Jennifer M</creator><creator>Moghaddam, Seyed J</creator><creator>Banerjee, Sulagna</creator><creator>Sahin, Ismet</creator><creator>Bhattacharya, Pratip</creator><creator>McAllister, Florencia</creator><general>Rockefeller University Press</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0003-3642-2144</orcidid><orcidid>https://orcid.org/0000-0003-0594-5102</orcidid><orcidid>https://orcid.org/0000-0002-2696-7995</orcidid><orcidid>https://orcid.org/0000-0003-2338-1662</orcidid><orcidid>https://orcid.org/0000-0002-9455-640X</orcidid><orcidid>https://orcid.org/0000-0002-6173-9074</orcidid><orcidid>https://orcid.org/0000-0002-0855-7124</orcidid><orcidid>https://orcid.org/0000-0002-1081-8231</orcidid><orcidid>https://orcid.org/0000-0001-7923-9978</orcidid><orcidid>https://orcid.org/0000-0003-4865-7071</orcidid><orcidid>https://orcid.org/0000-0002-9915-0943</orcidid><orcidid>https://orcid.org/0000-0002-8762-577X</orcidid><orcidid>https://orcid.org/0000-0002-4750-106X</orcidid><orcidid>https://orcid.org/0000-0002-5350-307X</orcidid><orcidid>https://orcid.org/0000-0003-3630-6696</orcidid><orcidid>https://orcid.org/0000-0002-5393-5606</orcidid></search><sort><creationdate>20201207</creationdate><title>Interleukin-17-induced neutrophil extracellular traps mediate resistance to checkpoint blockade in pancreatic cancer</title><author>Zhang, 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</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c450t-6959217401bcc126192317117e913e8bbb82bdb1e97d3976d7482f426da1bce43</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2020</creationdate><topic>Animals</topic><topic>Biomarkers, Tumor - metabolism</topic><topic>CD8-Positive T-Lymphocytes - drug effects</topic><topic>CD8-Positive T-Lymphocytes - immunology</topic><topic>Cell Line, Tumor</topic><topic>Drug Resistance, Neoplasm - drug effects</topic><topic>Extracellular Traps - metabolism</topic><topic>Humans</topic><topic>Immune Checkpoint Inhibitors - pharmacology</topic><topic>Immune Checkpoint Inhibitors - therapeutic use</topic><topic>Immunosuppression</topic><topic>Innate immunity and inflammation</topic><topic>Interleukin-17 - pharmacology</topic><topic>Lymphocyte Activation - drug effects</topic><topic>Mice, Inbred C57BL</topic><topic>Neutrophils - drug effects</topic><topic>Neutrophils - pathology</topic><topic>Pancreatic Neoplasms - drug therapy</topic><topic>Pancreatic Neoplasms - immunology</topic><topic>Pancreatic Neoplasms - pathology</topic><topic>Programmed Cell Death 1 Receptor - metabolism</topic><topic>Signal Transduction - drug effects</topic><topic>Solid Tumors</topic><topic>Tumor immunology</topic><topic>Tumor Microenvironment - drug effects</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Zhang, Yu</creatorcontrib><creatorcontrib>Chandra, Vidhi</creatorcontrib><creatorcontrib>Riquelme Sanchez, Erick</creatorcontrib><creatorcontrib>Dutta, Prasanta</creatorcontrib><creatorcontrib>Quesada, Pompeyo R</creatorcontrib><creatorcontrib>Rakoski, Amanda</creatorcontrib><creatorcontrib>Zoltan, Michelle</creatorcontrib><creatorcontrib>Arora, Nivedita</creatorcontrib><creatorcontrib>Baydogan, Seyda</creatorcontrib><creatorcontrib>Horne, William</creatorcontrib><creatorcontrib>Burks, Jared</creatorcontrib><creatorcontrib>Xu, Hanwen</creatorcontrib><creatorcontrib>Hussain, Perwez</creatorcontrib><creatorcontrib>Wang, Huamin</creatorcontrib><creatorcontrib>Gupta, Sonal</creatorcontrib><creatorcontrib>Maitra, Anirban</creatorcontrib><creatorcontrib>Bailey, Jennifer M</creatorcontrib><creatorcontrib>Moghaddam, Seyed J</creatorcontrib><creatorcontrib>Banerjee, Sulagna</creatorcontrib><creatorcontrib>Sahin, Ismet</creatorcontrib><creatorcontrib>Bhattacharya, Pratip</creatorcontrib><creatorcontrib>McAllister, Florencia</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>The Journal of experimental medicine</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Zhang, Yu</au><au>Chandra, Vidhi</au><au>Riquelme Sanchez, Erick</au><au>Dutta, Prasanta</au><au>Quesada, Pompeyo R</au><au>Rakoski, Amanda</au><au>Zoltan, Michelle</au><au>Arora, Nivedita</au><au>Baydogan, Seyda</au><au>Horne, William</au><au>Burks, Jared</au><au>Xu, Hanwen</au><au>Hussain, Perwez</au><au>Wang, Huamin</au><au>Gupta, Sonal</au><au>Maitra, Anirban</au><au>Bailey, Jennifer M</au><au>Moghaddam, Seyed J</au><au>Banerjee, Sulagna</au><au>Sahin, Ismet</au><au>Bhattacharya, Pratip</au><au>McAllister, Florencia</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Interleukin-17-induced neutrophil extracellular traps mediate resistance to checkpoint blockade in pancreatic cancer</atitle><jtitle>The Journal of experimental medicine</jtitle><addtitle>J Exp Med</addtitle><date>2020-12-07</date><risdate>2020</risdate><volume>217</volume><issue>12</issue><issn>0022-1007</issn><eissn>1540-9538</eissn><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.</abstract><cop>United States</cop><pub>Rockefeller University Press</pub><pmid>32860704</pmid><doi>10.1084/jem.20190354</doi><orcidid>https://orcid.org/0000-0003-3642-2144</orcidid><orcidid>https://orcid.org/0000-0003-0594-5102</orcidid><orcidid>https://orcid.org/0000-0002-2696-7995</orcidid><orcidid>https://orcid.org/0000-0003-2338-1662</orcidid><orcidid>https://orcid.org/0000-0002-9455-640X</orcidid><orcidid>https://orcid.org/0000-0002-6173-9074</orcidid><orcidid>https://orcid.org/0000-0002-0855-7124</orcidid><orcidid>https://orcid.org/0000-0002-1081-8231</orcidid><orcidid>https://orcid.org/0000-0001-7923-9978</orcidid><orcidid>https://orcid.org/0000-0003-4865-7071</orcidid><orcidid>https://orcid.org/0000-0002-9915-0943</orcidid><orcidid>https://orcid.org/0000-0002-8762-577X</orcidid><orcidid>https://orcid.org/0000-0002-4750-106X</orcidid><orcidid>https://orcid.org/0000-0002-5350-307X</orcidid><orcidid>https://orcid.org/0000-0003-3630-6696</orcidid><orcidid>https://orcid.org/0000-0002-5393-5606</orcidid><oa>free_for_read</oa></addata></record> |
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| subjects | Animals Biomarkers, Tumor - metabolism CD8-Positive T-Lymphocytes - drug effects CD8-Positive T-Lymphocytes - immunology Cell Line, Tumor Drug Resistance, Neoplasm - drug effects Extracellular Traps - metabolism Humans Immune Checkpoint Inhibitors - pharmacology Immune Checkpoint Inhibitors - therapeutic use Immunosuppression Innate immunity and inflammation Interleukin-17 - pharmacology Lymphocyte Activation - drug effects Mice, Inbred C57BL Neutrophils - drug effects Neutrophils - pathology Pancreatic Neoplasms - drug therapy Pancreatic Neoplasms - immunology Pancreatic Neoplasms - pathology Programmed Cell Death 1 Receptor - metabolism Signal Transduction - drug effects Solid Tumors Tumor immunology Tumor Microenvironment - drug effects |
| title | Interleukin-17-induced neutrophil extracellular traps mediate resistance to checkpoint blockade in pancreatic cancer |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-13T20%3A22%3A43IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-pubmed_cross&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Interleukin-17-induced%20neutrophil%20extracellular%20traps%20mediate%20resistance%20to%20checkpoint%20blockade%20in%20pancreatic%20cancer&rft.jtitle=The%20Journal%20of%20experimental%20medicine&rft.au=Zhang,%20Yu&rft.date=2020-12-07&rft.volume=217&rft.issue=12&rft.issn=0022-1007&rft.eissn=1540-9538&rft_id=info:doi/10.1084/jem.20190354&rft_dat=%3Cpubmed_cross%3E32860704%3C/pubmed_cross%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_id=info:pmid/32860704&rfr_iscdi=true |