Cytotoxic T Cells in PD-L1-Positive Malignant Pleural Mesotheliomas Are Counterbalanced by Distinct Immunosuppressive Factors
PD-L1 immunohistochemical staining does not always predict whether a cancer will respond to treatment with PD-1 inhibitors. We sought to characterize immune cell infiltrates and the expression of T-cell inhibitor markers in PD-L1-positive and PD-L1-negative malignant pleural mesothelioma samples. We...
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creator | Awad, Mark M Jones, Robert E Liu, Hongye Lizotte, Patrick H Ivanova, Elena V Kulkarni, Meghana Herter-Sprie, Grit S Liao, Xiaoyun Santos, Abigail A Bittinger, Mark A Keogh, Lauren Koyama, Shohei Almonte, Christina English, Jessie M Barlow, Julianne Richards, William G Barbie, David A Bass, Adam J Rodig, Scott J Hodi, F Stephen Wucherpfennig, Kai W Jänne, Pasi A Sholl, Lynette M Hammerman, Peter S Wong, Kwok-Kin Bueno, Raphael |
description | PD-L1 immunohistochemical staining does not always predict whether a cancer will respond to treatment with PD-1 inhibitors. We sought to characterize immune cell infiltrates and the expression of T-cell inhibitor markers in PD-L1-positive and PD-L1-negative malignant pleural mesothelioma samples. We developed a method for immune cell phenotyping using flow cytometry on solid tumors that have been dissociated into single-cell suspensions and applied this technique to analyze 43 resected malignant pleural mesothelioma specimens. Compared with PD-L1-negative tumors, PD-L1-positive tumors had significantly more infiltrating CD45
immune cells, a significantly higher proportion of infiltrating CD3
T cells, and a significantly higher percentage of CD3
cells displaying the activated HLA-DR
/CD38
phenotype. PD-L1-positive tumors also had a significantly higher proportion of proliferating CD8
T cells, a higher fraction of FOXP3
/CD4
Tregs, and increased expression of PD-1 and TIM-3 on CD4
and CD8
T cells. Double-positive PD-1
/TIM-3
CD8
T cells were more commonly found on PD-L1-positive tumors. Compared with epithelioid tumors, sarcomatoid and biphasic mesothelioma samples were significantly more likely to be PD-L1 positive and showed more infiltration with CD3
T cells and PD-1
/TIM-3
CD8
T cells. Immunologic phenotypes in mesothelioma differ based on PD-L1 status and histologic subtype. Successful incorporation of comprehensive immune profiling by flow cytometry into prospective clinical trials could refine our ability to predict which patients will respond to specific immune checkpoint blockade strategies. Cancer Immunol Res; 4(12); 1038-48. ©2016 AACR. |
doi_str_mv | 10.1158/2326-6066.CIR-16-0171 |
format | Article |
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immune cells, a significantly higher proportion of infiltrating CD3
T cells, and a significantly higher percentage of CD3
cells displaying the activated HLA-DR
/CD38
phenotype. PD-L1-positive tumors also had a significantly higher proportion of proliferating CD8
T cells, a higher fraction of FOXP3
/CD4
Tregs, and increased expression of PD-1 and TIM-3 on CD4
and CD8
T cells. Double-positive PD-1
/TIM-3
CD8
T cells were more commonly found on PD-L1-positive tumors. Compared with epithelioid tumors, sarcomatoid and biphasic mesothelioma samples were significantly more likely to be PD-L1 positive and showed more infiltration with CD3
T cells and PD-1
/TIM-3
CD8
T cells. Immunologic phenotypes in mesothelioma differ based on PD-L1 status and histologic subtype. Successful incorporation of comprehensive immune profiling by flow cytometry into prospective clinical trials could refine our ability to predict which patients will respond to specific immune checkpoint blockade strategies. Cancer Immunol Res; 4(12); 1038-48. ©2016 AACR.</description><identifier>ISSN: 2326-6066</identifier><identifier>EISSN: 2326-6074</identifier><identifier>DOI: 10.1158/2326-6066.CIR-16-0171</identifier><identifier>PMID: 27856426</identifier><language>eng</language><publisher>United States</publisher><subject>B7-H1 Antigen - immunology ; Female ; Humans ; Male ; Mesothelioma - immunology ; Pleural Neoplasms - immunology ; T-Lymphocytes, Cytotoxic - immunology</subject><ispartof>Cancer immunology research, 2016-12, Vol.4 (12), p.1038-1048</ispartof><rights>2016 American Association for Cancer Research.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c356t-84077037593f7ad15d846e8e078bf3acc6cac7ffed695a78800b8a01a01172d73</citedby><cites>FETCH-LOGICAL-c356t-84077037593f7ad15d846e8e078bf3acc6cac7ffed695a78800b8a01a01172d73</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,3356,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/27856426$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Awad, Mark M</creatorcontrib><creatorcontrib>Jones, Robert E</creatorcontrib><creatorcontrib>Liu, Hongye</creatorcontrib><creatorcontrib>Lizotte, Patrick H</creatorcontrib><creatorcontrib>Ivanova, Elena V</creatorcontrib><creatorcontrib>Kulkarni, Meghana</creatorcontrib><creatorcontrib>Herter-Sprie, Grit S</creatorcontrib><creatorcontrib>Liao, Xiaoyun</creatorcontrib><creatorcontrib>Santos, Abigail A</creatorcontrib><creatorcontrib>Bittinger, Mark A</creatorcontrib><creatorcontrib>Keogh, Lauren</creatorcontrib><creatorcontrib>Koyama, Shohei</creatorcontrib><creatorcontrib>Almonte, Christina</creatorcontrib><creatorcontrib>English, Jessie M</creatorcontrib><creatorcontrib>Barlow, Julianne</creatorcontrib><creatorcontrib>Richards, William G</creatorcontrib><creatorcontrib>Barbie, David A</creatorcontrib><creatorcontrib>Bass, Adam J</creatorcontrib><creatorcontrib>Rodig, Scott J</creatorcontrib><creatorcontrib>Hodi, F Stephen</creatorcontrib><creatorcontrib>Wucherpfennig, Kai W</creatorcontrib><creatorcontrib>Jänne, Pasi A</creatorcontrib><creatorcontrib>Sholl, Lynette M</creatorcontrib><creatorcontrib>Hammerman, Peter S</creatorcontrib><creatorcontrib>Wong, Kwok-Kin</creatorcontrib><creatorcontrib>Bueno, Raphael</creatorcontrib><title>Cytotoxic T Cells in PD-L1-Positive Malignant Pleural Mesotheliomas Are Counterbalanced by Distinct Immunosuppressive Factors</title><title>Cancer immunology research</title><addtitle>Cancer Immunol Res</addtitle><description>PD-L1 immunohistochemical staining does not always predict whether a cancer will respond to treatment with PD-1 inhibitors. We sought to characterize immune cell infiltrates and the expression of T-cell inhibitor markers in PD-L1-positive and PD-L1-negative malignant pleural mesothelioma samples. We developed a method for immune cell phenotyping using flow cytometry on solid tumors that have been dissociated into single-cell suspensions and applied this technique to analyze 43 resected malignant pleural mesothelioma specimens. Compared with PD-L1-negative tumors, PD-L1-positive tumors had significantly more infiltrating CD45
immune cells, a significantly higher proportion of infiltrating CD3
T cells, and a significantly higher percentage of CD3
cells displaying the activated HLA-DR
/CD38
phenotype. PD-L1-positive tumors also had a significantly higher proportion of proliferating CD8
T cells, a higher fraction of FOXP3
/CD4
Tregs, and increased expression of PD-1 and TIM-3 on CD4
and CD8
T cells. Double-positive PD-1
/TIM-3
CD8
T cells were more commonly found on PD-L1-positive tumors. Compared with epithelioid tumors, sarcomatoid and biphasic mesothelioma samples were significantly more likely to be PD-L1 positive and showed more infiltration with CD3
T cells and PD-1
/TIM-3
CD8
T cells. Immunologic phenotypes in mesothelioma differ based on PD-L1 status and histologic subtype. Successful incorporation of comprehensive immune profiling by flow cytometry into prospective clinical trials could refine our ability to predict which patients will respond to specific immune checkpoint blockade strategies. Cancer Immunol Res; 4(12); 1038-48. ©2016 AACR.</description><subject>B7-H1 Antigen - immunology</subject><subject>Female</subject><subject>Humans</subject><subject>Male</subject><subject>Mesothelioma - immunology</subject><subject>Pleural Neoplasms - immunology</subject><subject>T-Lymphocytes, Cytotoxic - immunology</subject><issn>2326-6066</issn><issn>2326-6074</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2016</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNo9kE1LxDAQhoMoKqs_QcnRSzXpR5I9Sv1aWHGR9RzSdKqRtlkzqbgH_7strg4DMwzvvMM8hJxxdsl5oa7SLBWJYEJclovnhIuEccn3yPFuLvP9_16II3KK-M7GUCrnRX5IjlKpCpGn4ph8l9voo_9ylq5pCW2L1PV0dZMsebLy6KL7BPpoWvfamz7SVQtDMC19BPTxDVrnO4P0OgAt_dBHCJVpTW-hptWW3jiMrreRLrpu6D0Om00AxMnxztjoA56Qg8a0CKe7OiMvd7fr8iFZPt0vyutlYrNCxETlTEqWyWKeNdLUvKhVLkABk6pqMmOtsMbKpoFazAsjlWKsUobxMblMa5nNyMWv7yb4jwEw6s6hHb81PfgBNR_ByLmYi3SUFr9SGzxigEZvgutM2GrO9ARfT2D1BFaP8DUXeoI_7p3vTgxVB_X_1h_q7Adwl4Et</recordid><startdate>201612</startdate><enddate>201612</enddate><creator>Awad, Mark M</creator><creator>Jones, Robert E</creator><creator>Liu, Hongye</creator><creator>Lizotte, Patrick H</creator><creator>Ivanova, Elena V</creator><creator>Kulkarni, Meghana</creator><creator>Herter-Sprie, Grit S</creator><creator>Liao, Xiaoyun</creator><creator>Santos, Abigail A</creator><creator>Bittinger, Mark A</creator><creator>Keogh, Lauren</creator><creator>Koyama, Shohei</creator><creator>Almonte, Christina</creator><creator>English, Jessie M</creator><creator>Barlow, Julianne</creator><creator>Richards, William G</creator><creator>Barbie, David A</creator><creator>Bass, Adam J</creator><creator>Rodig, Scott J</creator><creator>Hodi, F Stephen</creator><creator>Wucherpfennig, Kai W</creator><creator>Jänne, Pasi A</creator><creator>Sholl, Lynette M</creator><creator>Hammerman, Peter S</creator><creator>Wong, Kwok-Kin</creator><creator>Bueno, Raphael</creator><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>7X8</scope></search><sort><creationdate>201612</creationdate><title>Cytotoxic T Cells in PD-L1-Positive Malignant Pleural Mesotheliomas Are Counterbalanced by Distinct Immunosuppressive Factors</title><author>Awad, Mark M ; Jones, Robert E ; Liu, Hongye ; Lizotte, Patrick H ; Ivanova, Elena V ; Kulkarni, Meghana ; Herter-Sprie, Grit S ; Liao, Xiaoyun ; Santos, Abigail A ; Bittinger, Mark A ; Keogh, Lauren ; Koyama, Shohei ; Almonte, Christina ; English, Jessie M ; Barlow, Julianne ; Richards, William G ; Barbie, David A ; Bass, Adam J ; Rodig, Scott J ; Hodi, F Stephen ; Wucherpfennig, Kai W ; Jänne, Pasi A ; Sholl, Lynette M ; Hammerman, Peter S ; Wong, Kwok-Kin ; Bueno, Raphael</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c356t-84077037593f7ad15d846e8e078bf3acc6cac7ffed695a78800b8a01a01172d73</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2016</creationdate><topic>B7-H1 Antigen - immunology</topic><topic>Female</topic><topic>Humans</topic><topic>Male</topic><topic>Mesothelioma - immunology</topic><topic>Pleural Neoplasms - immunology</topic><topic>T-Lymphocytes, Cytotoxic - immunology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Awad, Mark M</creatorcontrib><creatorcontrib>Jones, Robert E</creatorcontrib><creatorcontrib>Liu, Hongye</creatorcontrib><creatorcontrib>Lizotte, Patrick H</creatorcontrib><creatorcontrib>Ivanova, Elena V</creatorcontrib><creatorcontrib>Kulkarni, Meghana</creatorcontrib><creatorcontrib>Herter-Sprie, Grit S</creatorcontrib><creatorcontrib>Liao, Xiaoyun</creatorcontrib><creatorcontrib>Santos, Abigail A</creatorcontrib><creatorcontrib>Bittinger, Mark A</creatorcontrib><creatorcontrib>Keogh, Lauren</creatorcontrib><creatorcontrib>Koyama, Shohei</creatorcontrib><creatorcontrib>Almonte, Christina</creatorcontrib><creatorcontrib>English, Jessie M</creatorcontrib><creatorcontrib>Barlow, Julianne</creatorcontrib><creatorcontrib>Richards, William G</creatorcontrib><creatorcontrib>Barbie, David A</creatorcontrib><creatorcontrib>Bass, Adam J</creatorcontrib><creatorcontrib>Rodig, Scott J</creatorcontrib><creatorcontrib>Hodi, F Stephen</creatorcontrib><creatorcontrib>Wucherpfennig, Kai W</creatorcontrib><creatorcontrib>Jänne, Pasi A</creatorcontrib><creatorcontrib>Sholl, Lynette M</creatorcontrib><creatorcontrib>Hammerman, Peter S</creatorcontrib><creatorcontrib>Wong, Kwok-Kin</creatorcontrib><creatorcontrib>Bueno, Raphael</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Cancer immunology research</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Awad, Mark M</au><au>Jones, Robert E</au><au>Liu, Hongye</au><au>Lizotte, Patrick H</au><au>Ivanova, Elena V</au><au>Kulkarni, Meghana</au><au>Herter-Sprie, Grit S</au><au>Liao, Xiaoyun</au><au>Santos, Abigail A</au><au>Bittinger, Mark A</au><au>Keogh, Lauren</au><au>Koyama, Shohei</au><au>Almonte, Christina</au><au>English, Jessie M</au><au>Barlow, Julianne</au><au>Richards, William G</au><au>Barbie, David A</au><au>Bass, Adam J</au><au>Rodig, Scott J</au><au>Hodi, F Stephen</au><au>Wucherpfennig, Kai W</au><au>Jänne, Pasi A</au><au>Sholl, Lynette M</au><au>Hammerman, Peter S</au><au>Wong, Kwok-Kin</au><au>Bueno, Raphael</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Cytotoxic T Cells in PD-L1-Positive Malignant Pleural Mesotheliomas Are Counterbalanced by Distinct Immunosuppressive Factors</atitle><jtitle>Cancer immunology research</jtitle><addtitle>Cancer Immunol Res</addtitle><date>2016-12</date><risdate>2016</risdate><volume>4</volume><issue>12</issue><spage>1038</spage><epage>1048</epage><pages>1038-1048</pages><issn>2326-6066</issn><eissn>2326-6074</eissn><abstract>PD-L1 immunohistochemical staining does not always predict whether a cancer will respond to treatment with PD-1 inhibitors. We sought to characterize immune cell infiltrates and the expression of T-cell inhibitor markers in PD-L1-positive and PD-L1-negative malignant pleural mesothelioma samples. We developed a method for immune cell phenotyping using flow cytometry on solid tumors that have been dissociated into single-cell suspensions and applied this technique to analyze 43 resected malignant pleural mesothelioma specimens. Compared with PD-L1-negative tumors, PD-L1-positive tumors had significantly more infiltrating CD45
immune cells, a significantly higher proportion of infiltrating CD3
T cells, and a significantly higher percentage of CD3
cells displaying the activated HLA-DR
/CD38
phenotype. PD-L1-positive tumors also had a significantly higher proportion of proliferating CD8
T cells, a higher fraction of FOXP3
/CD4
Tregs, and increased expression of PD-1 and TIM-3 on CD4
and CD8
T cells. Double-positive PD-1
/TIM-3
CD8
T cells were more commonly found on PD-L1-positive tumors. Compared with epithelioid tumors, sarcomatoid and biphasic mesothelioma samples were significantly more likely to be PD-L1 positive and showed more infiltration with CD3
T cells and PD-1
/TIM-3
CD8
T cells. Immunologic phenotypes in mesothelioma differ based on PD-L1 status and histologic subtype. Successful incorporation of comprehensive immune profiling by flow cytometry into prospective clinical trials could refine our ability to predict which patients will respond to specific immune checkpoint blockade strategies. Cancer Immunol Res; 4(12); 1038-48. ©2016 AACR.</abstract><cop>United States</cop><pmid>27856426</pmid><doi>10.1158/2326-6066.CIR-16-0171</doi><tpages>11</tpages><oa>free_for_read</oa></addata></record> |
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source | MEDLINE; American Association for Cancer Research; EZB-FREE-00999 freely available EZB journals |
subjects | B7-H1 Antigen - immunology Female Humans Male Mesothelioma - immunology Pleural Neoplasms - immunology T-Lymphocytes, Cytotoxic - immunology |
title | Cytotoxic T Cells in PD-L1-Positive Malignant Pleural Mesotheliomas Are Counterbalanced by Distinct Immunosuppressive Factors |
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