Monitoring and functional characterization of the lymphocytic compartment in pancreatic ductal adenocarcinoma patients
Abstract Background/Objectives Pancreatic ductal adenocarcinoma (PDAC) still has a poor prognosis and current treatments including immunotherapy often fail. This might be due to the pronounced immunosuppressive milieu impairing infiltration and function of immune effector cells. This study aimed at...
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| Veröffentlicht in: | Pancreatology : official journal of the International Association of Pancreatology (IAP) ... [et al.] 2016-11, Vol.16 (6), p.1069-1079 |
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| creator | Oberg, Hans-Heinrich Grage-Griebenow, Evelin Adam-Klages, Sabine Jerg, Elfi Peipp, Matthias Kellner, Christian Petrick, Domantas Gonnermann, Daniel Freitag-Wolf, Sandra Röcken, Christoph Sebens, Thorsten Vogel, Ilka Becker, Thomas Ebsen, Michael Kabelitz, Dieter Wesch, Daniela Sebens, Susanne |
| description | Abstract Background/Objectives Pancreatic ductal adenocarcinoma (PDAC) still has a poor prognosis and current treatments including immunotherapy often fail. This might be due to the pronounced immunosuppressive milieu impairing infiltration and function of immune effector cells. This study aimed at a comprehensive analysis of immune cells in PDAC patients by determining absolute and relative peripheral blood cell numbers of immune cell subsets along with their functional capacity. Methods Whole blood cells or isolated peripheral blood mononuclear cells were characterized by flow cytometry. PDAC tissues were analyzed by immunohistochemistry. Anti-tumor activity of immune effector cells was determined by RTCA system. Results Our data demonstrate that relative CD4+ memory- and regulatory T cell numbers were enhanced, whereas determination of absolute cell numbers revealed generally lower immune cell numbers in PDAC patients compared to healthy controls. γδ T cells accumulated at higher numbers compared to αβ T cells in the malignant ductal epithelium of PDAC tissues indicating that γδ T cells infiltrate into the tumor. Cytotoxicity against tumor cells of even small numbers of T- and NK cells could be induced by a bispecific antibody targeting CD3+ T cells to human epidermal growth factor receptor (HER)2 expressing PDAC cells or Trastuzumab. Importantly, a critical number of γδ T cells was required for significant tumor cell killing by a bispecific antibody engaging the γδ T cell receptor on γδ T cells and HER2 on tumor cells. Conclusion Monitoring immune cells along with the determination of their functional capacity provides a comprehensive assessment as a prerequisite for a personalized immunotherapeutic PDAC treatment. |
| doi_str_mv | 10.1016/j.pan.2016.07.008 |
| format | Article |
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This might be due to the pronounced immunosuppressive milieu impairing infiltration and function of immune effector cells. This study aimed at a comprehensive analysis of immune cells in PDAC patients by determining absolute and relative peripheral blood cell numbers of immune cell subsets along with their functional capacity. Methods Whole blood cells or isolated peripheral blood mononuclear cells were characterized by flow cytometry. PDAC tissues were analyzed by immunohistochemistry. Anti-tumor activity of immune effector cells was determined by RTCA system. Results Our data demonstrate that relative CD4+ memory- and regulatory T cell numbers were enhanced, whereas determination of absolute cell numbers revealed generally lower immune cell numbers in PDAC patients compared to healthy controls. γδ T cells accumulated at higher numbers compared to αβ T cells in the malignant ductal epithelium of PDAC tissues indicating that γδ T cells infiltrate into the tumor. Cytotoxicity against tumor cells of even small numbers of T- and NK cells could be induced by a bispecific antibody targeting CD3+ T cells to human epidermal growth factor receptor (HER)2 expressing PDAC cells or Trastuzumab. Importantly, a critical number of γδ T cells was required for significant tumor cell killing by a bispecific antibody engaging the γδ T cell receptor on γδ T cells and HER2 on tumor cells. Conclusion Monitoring immune cells along with the determination of their functional capacity provides a comprehensive assessment as a prerequisite for a personalized immunotherapeutic PDAC treatment.</description><identifier>ISSN: 1424-3903</identifier><identifier>EISSN: 1424-3911</identifier><identifier>DOI: 10.1016/j.pan.2016.07.008</identifier><identifier>PMID: 27424476</identifier><language>eng</language><publisher>Switzerland: Elsevier B.V</publisher><subject>Age ; Antineoplastic Agents - therapeutic use ; Carcinoma, Pancreatic Ductal - drug therapy ; Carcinoma, Pancreatic Ductal - immunology ; Carcinoma, Pancreatic Ductal - pathology ; CD4-Positive T-Lymphocytes - immunology ; Chemotherapy ; Cloning ; Endocrinology & Metabolism ; Epithelium - pathology ; Female ; Flow Cytometry ; Gastroenterology and Hepatology ; Humans ; Immune escape ; Immune status ; Immune therapy ; Immunohistochemistry ; Immunotherapy ; Leukocyte Count ; Lymphatic system ; Lymphocytes ; Lymphocytes - immunology ; Male ; Medical prognosis ; Middle Aged ; Monitoring, Physiologic ; Pancreatic cancer ; Pancreatic Ducts - pathology ; Pancreatic Neoplasms - drug therapy ; Pancreatic Neoplasms - immunology ; Pancreatic Neoplasms - pathology ; Patients ; Receptor, ErbB-2 - genetics ; Receptor, ErbB-2 - metabolism ; T-Lymphocytes, Regulatory - immunology ; Thoracic surgery ; Trastuzumab - therapeutic use ; γδ T cells</subject><ispartof>Pancreatology : official journal of the International Association of Pancreatology (IAP) ... [et al.], 2016-11, Vol.16 (6), p.1069-1079</ispartof><rights>2016 IAP and EPC</rights><rights>Copyright © 2016 IAP and EPC. Published by Elsevier B.V. All rights reserved.</rights><rights>Copyright Elsevier Limited Nov/Dec 2016</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c469t-28ab95cb671a8c5750b5adea53ee108f220a4ab4bb5b3d0c133ff153221a7cfb3</citedby><cites>FETCH-LOGICAL-c469t-28ab95cb671a8c5750b5adea53ee108f220a4ab4bb5b3d0c133ff153221a7cfb3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,27923,27924</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/27424476$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Oberg, Hans-Heinrich</creatorcontrib><creatorcontrib>Grage-Griebenow, Evelin</creatorcontrib><creatorcontrib>Adam-Klages, Sabine</creatorcontrib><creatorcontrib>Jerg, Elfi</creatorcontrib><creatorcontrib>Peipp, Matthias</creatorcontrib><creatorcontrib>Kellner, Christian</creatorcontrib><creatorcontrib>Petrick, Domantas</creatorcontrib><creatorcontrib>Gonnermann, Daniel</creatorcontrib><creatorcontrib>Freitag-Wolf, Sandra</creatorcontrib><creatorcontrib>Röcken, Christoph</creatorcontrib><creatorcontrib>Sebens, Thorsten</creatorcontrib><creatorcontrib>Vogel, Ilka</creatorcontrib><creatorcontrib>Becker, Thomas</creatorcontrib><creatorcontrib>Ebsen, Michael</creatorcontrib><creatorcontrib>Kabelitz, Dieter</creatorcontrib><creatorcontrib>Wesch, Daniela</creatorcontrib><creatorcontrib>Sebens, Susanne</creatorcontrib><title>Monitoring and functional characterization of the lymphocytic compartment in pancreatic ductal adenocarcinoma patients</title><title>Pancreatology : official journal of the International Association of Pancreatology (IAP) ... [et al.]</title><addtitle>Pancreatology</addtitle><description>Abstract Background/Objectives Pancreatic ductal adenocarcinoma (PDAC) still has a poor prognosis and current treatments including immunotherapy often fail. This might be due to the pronounced immunosuppressive milieu impairing infiltration and function of immune effector cells. This study aimed at a comprehensive analysis of immune cells in PDAC patients by determining absolute and relative peripheral blood cell numbers of immune cell subsets along with their functional capacity. Methods Whole blood cells or isolated peripheral blood mononuclear cells were characterized by flow cytometry. PDAC tissues were analyzed by immunohistochemistry. Anti-tumor activity of immune effector cells was determined by RTCA system. Results Our data demonstrate that relative CD4+ memory- and regulatory T cell numbers were enhanced, whereas determination of absolute cell numbers revealed generally lower immune cell numbers in PDAC patients compared to healthy controls. γδ T cells accumulated at higher numbers compared to αβ T cells in the malignant ductal epithelium of PDAC tissues indicating that γδ T cells infiltrate into the tumor. Cytotoxicity against tumor cells of even small numbers of T- and NK cells could be induced by a bispecific antibody targeting CD3+ T cells to human epidermal growth factor receptor (HER)2 expressing PDAC cells or Trastuzumab. Importantly, a critical number of γδ T cells was required for significant tumor cell killing by a bispecific antibody engaging the γδ T cell receptor on γδ T cells and HER2 on tumor cells. Conclusion Monitoring immune cells along with the determination of their functional capacity provides a comprehensive assessment as a prerequisite for a personalized immunotherapeutic PDAC treatment.</description><subject>Age</subject><subject>Antineoplastic Agents - therapeutic use</subject><subject>Carcinoma, Pancreatic Ductal - drug therapy</subject><subject>Carcinoma, Pancreatic Ductal - immunology</subject><subject>Carcinoma, Pancreatic Ductal - pathology</subject><subject>CD4-Positive T-Lymphocytes - immunology</subject><subject>Chemotherapy</subject><subject>Cloning</subject><subject>Endocrinology & Metabolism</subject><subject>Epithelium - pathology</subject><subject>Female</subject><subject>Flow Cytometry</subject><subject>Gastroenterology and Hepatology</subject><subject>Humans</subject><subject>Immune escape</subject><subject>Immune status</subject><subject>Immune therapy</subject><subject>Immunohistochemistry</subject><subject>Immunotherapy</subject><subject>Leukocyte Count</subject><subject>Lymphatic system</subject><subject>Lymphocytes</subject><subject>Lymphocytes - immunology</subject><subject>Male</subject><subject>Medical prognosis</subject><subject>Middle Aged</subject><subject>Monitoring, Physiologic</subject><subject>Pancreatic cancer</subject><subject>Pancreatic Ducts - pathology</subject><subject>Pancreatic Neoplasms - drug therapy</subject><subject>Pancreatic Neoplasms - immunology</subject><subject>Pancreatic Neoplasms - pathology</subject><subject>Patients</subject><subject>Receptor, ErbB-2 - genetics</subject><subject>Receptor, ErbB-2 - metabolism</subject><subject>T-Lymphocytes, Regulatory - immunology</subject><subject>Thoracic surgery</subject><subject>Trastuzumab - therapeutic use</subject><subject>γδ T cells</subject><issn>1424-3903</issn><issn>1424-3911</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2016</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqNkl-L1TAQxYso7h_9AL5IwRdfbs2kadKLICyLrsKKD-pzmE5Tb65tUpN04frpTb3rCvsgPmXI_OaQOSdF8QxYBQzkq301o6t4LiumKsbaB8UpCC429Rbg4V3N6pPiLMY9Y5wDbB8XJ1zljlDytLj56J1NPlj3rUTXl8PiKFnvcCxphwEpmWB_4npV-qFMO1OOh2neeTokSyX5acaQJuNSaV2Zn0PB4NrpF0pZBHvjPGEg6_yEGUg2s_FJ8WjAMZqnt-d58fXd2y-X7zfXn64-XF5cb0jIbdrwFrttQ51UgC01qmFdkxWxqY0B1g6cMxTYia5rurpnBHU9DNDUeU9UNHT1efHyqDsH_2MxMenJRjLjiM74JWpohRQgoIX_QLlUnDdSZPTFPXTvl5A9-y0ISsq2WSk4UhR8jMEMeg52wnDQwPSan97rbJhe89NM6Zxfnnl-q7x0k-nvJv4EloHXR8Bk126sCTpSdpRMb4OhpHtv_yn_5t40jdZZwvG7OZj4dwsduWb68_qB1v8DsgYQStS_AF_YwgE</recordid><startdate>20161101</startdate><enddate>20161101</enddate><creator>Oberg, Hans-Heinrich</creator><creator>Grage-Griebenow, Evelin</creator><creator>Adam-Klages, Sabine</creator><creator>Jerg, Elfi</creator><creator>Peipp, Matthias</creator><creator>Kellner, Christian</creator><creator>Petrick, Domantas</creator><creator>Gonnermann, Daniel</creator><creator>Freitag-Wolf, Sandra</creator><creator>Röcken, Christoph</creator><creator>Sebens, Thorsten</creator><creator>Vogel, Ilka</creator><creator>Becker, Thomas</creator><creator>Ebsen, Michael</creator><creator>Kabelitz, Dieter</creator><creator>Wesch, Daniela</creator><creator>Sebens, Susanne</creator><general>Elsevier B.V</general><general>Elsevier Limited</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>7T5</scope><scope>H94</scope><scope>K9.</scope><scope>NAPCQ</scope><scope>7X8</scope></search><sort><creationdate>20161101</creationdate><title>Monitoring and functional characterization of the lymphocytic compartment in pancreatic ductal adenocarcinoma patients</title><author>Oberg, Hans-Heinrich ; Grage-Griebenow, Evelin ; Adam-Klages, Sabine ; Jerg, Elfi ; Peipp, Matthias ; Kellner, Christian ; Petrick, Domantas ; Gonnermann, Daniel ; Freitag-Wolf, Sandra ; Röcken, Christoph ; Sebens, Thorsten ; Vogel, Ilka ; Becker, Thomas ; Ebsen, Michael ; Kabelitz, Dieter ; Wesch, Daniela ; Sebens, Susanne</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c469t-28ab95cb671a8c5750b5adea53ee108f220a4ab4bb5b3d0c133ff153221a7cfb3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2016</creationdate><topic>Age</topic><topic>Antineoplastic Agents - therapeutic use</topic><topic>Carcinoma, Pancreatic Ductal - drug therapy</topic><topic>Carcinoma, Pancreatic Ductal - immunology</topic><topic>Carcinoma, Pancreatic Ductal - pathology</topic><topic>CD4-Positive T-Lymphocytes - immunology</topic><topic>Chemotherapy</topic><topic>Cloning</topic><topic>Endocrinology & Metabolism</topic><topic>Epithelium - pathology</topic><topic>Female</topic><topic>Flow Cytometry</topic><topic>Gastroenterology and Hepatology</topic><topic>Humans</topic><topic>Immune escape</topic><topic>Immune status</topic><topic>Immune therapy</topic><topic>Immunohistochemistry</topic><topic>Immunotherapy</topic><topic>Leukocyte Count</topic><topic>Lymphatic system</topic><topic>Lymphocytes</topic><topic>Lymphocytes - immunology</topic><topic>Male</topic><topic>Medical prognosis</topic><topic>Middle Aged</topic><topic>Monitoring, Physiologic</topic><topic>Pancreatic cancer</topic><topic>Pancreatic Ducts - pathology</topic><topic>Pancreatic Neoplasms - drug therapy</topic><topic>Pancreatic Neoplasms - immunology</topic><topic>Pancreatic Neoplasms - pathology</topic><topic>Patients</topic><topic>Receptor, ErbB-2 - genetics</topic><topic>Receptor, ErbB-2 - metabolism</topic><topic>T-Lymphocytes, Regulatory - immunology</topic><topic>Thoracic surgery</topic><topic>Trastuzumab - therapeutic use</topic><topic>γδ T cells</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Oberg, Hans-Heinrich</creatorcontrib><creatorcontrib>Grage-Griebenow, Evelin</creatorcontrib><creatorcontrib>Adam-Klages, Sabine</creatorcontrib><creatorcontrib>Jerg, Elfi</creatorcontrib><creatorcontrib>Peipp, Matthias</creatorcontrib><creatorcontrib>Kellner, Christian</creatorcontrib><creatorcontrib>Petrick, Domantas</creatorcontrib><creatorcontrib>Gonnermann, Daniel</creatorcontrib><creatorcontrib>Freitag-Wolf, Sandra</creatorcontrib><creatorcontrib>Röcken, Christoph</creatorcontrib><creatorcontrib>Sebens, Thorsten</creatorcontrib><creatorcontrib>Vogel, Ilka</creatorcontrib><creatorcontrib>Becker, Thomas</creatorcontrib><creatorcontrib>Ebsen, Michael</creatorcontrib><creatorcontrib>Kabelitz, Dieter</creatorcontrib><creatorcontrib>Wesch, Daniela</creatorcontrib><creatorcontrib>Sebens, Susanne</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Immunology Abstracts</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Nursing & Allied Health Premium</collection><collection>MEDLINE - Academic</collection><jtitle>Pancreatology : official journal of the International Association of Pancreatology (IAP) ... [et al.]</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Oberg, Hans-Heinrich</au><au>Grage-Griebenow, Evelin</au><au>Adam-Klages, Sabine</au><au>Jerg, Elfi</au><au>Peipp, Matthias</au><au>Kellner, Christian</au><au>Petrick, Domantas</au><au>Gonnermann, Daniel</au><au>Freitag-Wolf, Sandra</au><au>Röcken, Christoph</au><au>Sebens, Thorsten</au><au>Vogel, Ilka</au><au>Becker, Thomas</au><au>Ebsen, Michael</au><au>Kabelitz, Dieter</au><au>Wesch, Daniela</au><au>Sebens, Susanne</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Monitoring and functional characterization of the lymphocytic compartment in pancreatic ductal adenocarcinoma patients</atitle><jtitle>Pancreatology : official journal of the International Association of Pancreatology (IAP) ... [et al.]</jtitle><addtitle>Pancreatology</addtitle><date>2016-11-01</date><risdate>2016</risdate><volume>16</volume><issue>6</issue><spage>1069</spage><epage>1079</epage><pages>1069-1079</pages><issn>1424-3903</issn><eissn>1424-3911</eissn><abstract>Abstract Background/Objectives Pancreatic ductal adenocarcinoma (PDAC) still has a poor prognosis and current treatments including immunotherapy often fail. This might be due to the pronounced immunosuppressive milieu impairing infiltration and function of immune effector cells. This study aimed at a comprehensive analysis of immune cells in PDAC patients by determining absolute and relative peripheral blood cell numbers of immune cell subsets along with their functional capacity. Methods Whole blood cells or isolated peripheral blood mononuclear cells were characterized by flow cytometry. PDAC tissues were analyzed by immunohistochemistry. Anti-tumor activity of immune effector cells was determined by RTCA system. Results Our data demonstrate that relative CD4+ memory- and regulatory T cell numbers were enhanced, whereas determination of absolute cell numbers revealed generally lower immune cell numbers in PDAC patients compared to healthy controls. γδ T cells accumulated at higher numbers compared to αβ T cells in the malignant ductal epithelium of PDAC tissues indicating that γδ T cells infiltrate into the tumor. Cytotoxicity against tumor cells of even small numbers of T- and NK cells could be induced by a bispecific antibody targeting CD3+ T cells to human epidermal growth factor receptor (HER)2 expressing PDAC cells or Trastuzumab. Importantly, a critical number of γδ T cells was required for significant tumor cell killing by a bispecific antibody engaging the γδ T cell receptor on γδ T cells and HER2 on tumor cells. Conclusion Monitoring immune cells along with the determination of their functional capacity provides a comprehensive assessment as a prerequisite for a personalized immunotherapeutic PDAC treatment.</abstract><cop>Switzerland</cop><pub>Elsevier B.V</pub><pmid>27424476</pmid><doi>10.1016/j.pan.2016.07.008</doi><tpages>11</tpages></addata></record> |
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| ispartof | Pancreatology : official journal of the International Association of Pancreatology (IAP) ... [et al.], 2016-11, Vol.16 (6), p.1069-1079 |
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| subjects | Age Antineoplastic Agents - therapeutic use Carcinoma, Pancreatic Ductal - drug therapy Carcinoma, Pancreatic Ductal - immunology Carcinoma, Pancreatic Ductal - pathology CD4-Positive T-Lymphocytes - immunology Chemotherapy Cloning Endocrinology & Metabolism Epithelium - pathology Female Flow Cytometry Gastroenterology and Hepatology Humans Immune escape Immune status Immune therapy Immunohistochemistry Immunotherapy Leukocyte Count Lymphatic system Lymphocytes Lymphocytes - immunology Male Medical prognosis Middle Aged Monitoring, Physiologic Pancreatic cancer Pancreatic Ducts - pathology Pancreatic Neoplasms - drug therapy Pancreatic Neoplasms - immunology Pancreatic Neoplasms - pathology Patients Receptor, ErbB-2 - genetics Receptor, ErbB-2 - metabolism T-Lymphocytes, Regulatory - immunology Thoracic surgery Trastuzumab - therapeutic use γδ T cells |
| title | Monitoring and functional characterization of the lymphocytic compartment in pancreatic ductal adenocarcinoma patients |
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