Granzyme B is correlated with clinical outcome after PD-1 blockade in patients with stage IV non-small-cell lung cancer
BackgroundA minority of patients with advanced non-small-cell lung cancer (NSCLC) benefit from treatment with immune checkpoint inhibitors (ICIs). Ineffective effector function of activated T and NK cells may lead to reduced tumor cell death, even when these activated effector cells are released fro...
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| Veröffentlicht in: | Journal for immunotherapy of cancer 2020-05, Vol.8 (1), p.e000586, Article 000586 |
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| creator | Hurkmans, Daan P. Basak, Edwin A. Schepers, Nina Oomen-De Hoop, Esther Van der Leest, Cor H. El Bouazzaoui, Samira Bins, Sander Koolen, Stijn L. W. Sleijfer, Stefan Van der Veldt, Astrid A. M. Debets, Reno Van Schaik, Ron H. N. Aerts, Joachim G. J. V. Mathijssen, Ron H. J. |
| description | BackgroundA minority of patients with advanced non-small-cell lung cancer (NSCLC) benefit from treatment with immune checkpoint inhibitors (ICIs). Ineffective effector function of activated T and NK cells may lead to reduced tumor cell death, even when these activated effector cells are released from their immune checkpoint brake. Hence, in this study we aimed to assess the association of baseline serum granzyme B, as well as germline variation of the GZMB gene, with clinical outcome to programmed cell death protein 1 (PD-1) blockade.MethodsA total of 347 patients with stage IV NSCLC who started nivolumab treatment between June 2013 and June 2017 were prospectively included. Baseline serum and whole blood was available, allowing for protein quantification and targeted DNA sequencing. Clinical outcome was based on best overall response (BOR) according to Response Evaluation Criteria in Solid Tumors, V.1.1, progression-free survival (PFS), and overall survival (OS).ResultsPatients with low serum levels of granzyme B had worse PFS (HR: 1.96; 95% CI: 1.12 to 3.43; p=0.018) and worse OS (HR: 2.08; 95% CI: 1.12 to 3.87; p=0.021) than patients with high baseline serum levels. To validate the findings, germline variation of GZMB rs8192917 was assessed. Patients with homozygous and heterozygous variants of GZMB rs8192917 had worse BOR (OR: 1.60; 95% CI: 1.01 to 2.52; p=0.044) and worse PFS (HR: 1.38; 95% CI:1.02 to 1.87; p=0.036) than wild types.ConclusionsA low baseline serum level of granzyme B and germline variation of GZMB was associated with worse clinical outcome in NSCLC, emphasizing the relevance and additional value of monitoring germline genetic variations which mirror cytotoxic functions of T cells in ICI therapy.Trail registration numberDutch Trial Registry (NL6828). |
| doi_str_mv | 10.1136/jitc-2020-000586 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_webof</sourceid><recordid>TN_cdi_proquest_miscellaneous_2407582295</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><doaj_id>oai_doaj_org_article_81ec1929bfab4cc5a86e10e660b32778</doaj_id><sourcerecordid>2552987227</sourcerecordid><originalsourceid>FETCH-LOGICAL-b563t-7aabe2ef75846021a8e3d687b927bdbab3e826bda030d8fc4c202af189c0d1153</originalsourceid><addsrcrecordid>eNqNks1rFDEYxgdRbKm9e5KAF0FHk8wkk7kIumpdKOhBvYYk884260yyJhmX-tebceq2FYSeEpLf8_B-PEXxmOCXhFT81dYmU1JMcYkxZoLfK44pZqQkNeX3b9yPitMYt5khuKqEEA-Lo4rWnFS1OC72Z0G5X5cjoLfIRmR8CDCoBB3a23SBzGCdNWpAfkrGZ0r1CQL6_K4kSA_efFcdIOvQTiULLsVFFZPaAFp_Q867Mo5qGEoDw4CGyW2QUc5AeFQ86NUQ4fTqPCm-fnj_ZfWxPP90tl69OS8141UqG6U0UOgbJmqOKVECqo6LRre00Z1WugJBue4UrnAnelObPBDVE9Ea3BHCqpNivfh2Xm3lLthRhUvplZV_HnzYSBWSNQNIQcCQlra6V7o2hinBgWDgHOuKNo3IXq8Xr92kR-hMbjio4Zbp7R9nL-TG_5QNZTVhdTZ4dmUQ_I8JYpKjjfNklAM_RUlrnBultJ3rfvoPuvVTcHlUkjJGW9FQ2mQKL5QJPsYA_aEYguUcEjmHRM4hkUtIsuTJzSYOgr-RyIBYgD1o30eT92rggM0unBLcsjlQbGVT3rx3Kz-5lKXP7y69pvW4vUvdL67pwyz-i_8G_v_0Vg</addsrcrecordid><sourcetype>Open Website</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>2552987227</pqid></control><display><type>article</type><title>Granzyme B is correlated with clinical outcome after PD-1 blockade in patients with stage IV non-small-cell lung cancer</title><source>BMJ Open Access Journals</source><source>DOAJ Directory of Open Access Journals</source><source>EZB-FREE-00999 freely available EZB journals</source><source>PubMed Central</source><creator>Hurkmans, Daan P. ; Basak, Edwin A. ; Schepers, Nina ; Oomen-De Hoop, Esther ; Van der Leest, Cor H. ; El Bouazzaoui, Samira ; Bins, Sander ; Koolen, Stijn L. W. ; Sleijfer, Stefan ; Van der Veldt, Astrid A. M. ; Debets, Reno ; Van Schaik, Ron H. N. ; Aerts, Joachim G. J. V. ; Mathijssen, Ron H. J.</creator><creatorcontrib>Hurkmans, Daan P. ; Basak, Edwin A. ; Schepers, Nina ; Oomen-De Hoop, Esther ; Van der Leest, Cor H. ; El Bouazzaoui, Samira ; Bins, Sander ; Koolen, Stijn L. W. ; Sleijfer, Stefan ; Van der Veldt, Astrid A. M. ; Debets, Reno ; Van Schaik, Ron H. N. ; Aerts, Joachim G. J. V. ; Mathijssen, Ron H. J.</creatorcontrib><description>BackgroundA minority of patients with advanced non-small-cell lung cancer (NSCLC) benefit from treatment with immune checkpoint inhibitors (ICIs). Ineffective effector function of activated T and NK cells may lead to reduced tumor cell death, even when these activated effector cells are released from their immune checkpoint brake. Hence, in this study we aimed to assess the association of baseline serum granzyme B, as well as germline variation of the GZMB gene, with clinical outcome to programmed cell death protein 1 (PD-1) blockade.MethodsA total of 347 patients with stage IV NSCLC who started nivolumab treatment between June 2013 and June 2017 were prospectively included. Baseline serum and whole blood was available, allowing for protein quantification and targeted DNA sequencing. Clinical outcome was based on best overall response (BOR) according to Response Evaluation Criteria in Solid Tumors, V.1.1, progression-free survival (PFS), and overall survival (OS).ResultsPatients with low serum levels of granzyme B had worse PFS (HR: 1.96; 95% CI: 1.12 to 3.43; p=0.018) and worse OS (HR: 2.08; 95% CI: 1.12 to 3.87; p=0.021) than patients with high baseline serum levels. To validate the findings, germline variation of GZMB rs8192917 was assessed. Patients with homozygous and heterozygous variants of GZMB rs8192917 had worse BOR (OR: 1.60; 95% CI: 1.01 to 2.52; p=0.044) and worse PFS (HR: 1.38; 95% CI:1.02 to 1.87; p=0.036) than wild types.ConclusionsA low baseline serum level of granzyme B and germline variation of GZMB was associated with worse clinical outcome in NSCLC, emphasizing the relevance and additional value of monitoring germline genetic variations which mirror cytotoxic functions of T cells in ICI therapy.Trail registration numberDutch Trial Registry (NL6828).</description><identifier>ISSN: 2051-1426</identifier><identifier>EISSN: 2051-1426</identifier><identifier>DOI: 10.1136/jitc-2020-000586</identifier><identifier>PMID: 32461348</identifier><language>eng</language><publisher>LONDON: BMJ Publishing Group Ltd</publisher><subject>Apoptosis ; Cancer ; Cell death ; Clinical outcomes ; Clinical/Translational Cancer Immunotherapy ; Disease ; Flow cytometry ; genetic markers ; Immunology ; Immunotherapy ; Life Sciences & Biomedicine ; Lung cancer ; lung neoplasms ; Lymphocytes ; Oncology ; Patients ; programmed cell death 1 receptor ; Proteins ; Regression analysis ; Science & Technology ; T cell receptors ; translational medical research</subject><ispartof>Journal for immunotherapy of cancer, 2020-05, Vol.8 (1), p.e000586, Article 000586</ispartof><rights>Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.</rights><rights>2020 Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ. http://creativecommons.org/licenses/by-nc/4.0/ This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See http://creativecommons.org/licenses/by-nc/4.0/ . Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ. 2020</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>true</woscitedreferencessubscribed><woscitedreferencescount>47</woscitedreferencescount><woscitedreferencesoriginalsourcerecordid>wos000562109500015</woscitedreferencesoriginalsourcerecordid><citedby>FETCH-LOGICAL-b563t-7aabe2ef75846021a8e3d687b927bdbab3e826bda030d8fc4c202af189c0d1153</citedby><cites>FETCH-LOGICAL-b563t-7aabe2ef75846021a8e3d687b927bdbab3e826bda030d8fc4c202af189c0d1153</cites><orcidid>0000-0002-8750-5188 ; 0000-0002-0973-7530</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://jitc.bmj.com/content/8/1/e000586.full.pdf$$EPDF$$P50$$Gbmj$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://jitc.bmj.com/content/8/1/e000586.full$$EHTML$$P50$$Gbmj$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,2095,2107,27528,27529,27903,27904,53769,53771,55328,77347,77378,77406,77432</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/32461348$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Hurkmans, Daan P.</creatorcontrib><creatorcontrib>Basak, Edwin A.</creatorcontrib><creatorcontrib>Schepers, Nina</creatorcontrib><creatorcontrib>Oomen-De Hoop, Esther</creatorcontrib><creatorcontrib>Van der Leest, Cor H.</creatorcontrib><creatorcontrib>El Bouazzaoui, Samira</creatorcontrib><creatorcontrib>Bins, Sander</creatorcontrib><creatorcontrib>Koolen, Stijn L. W.</creatorcontrib><creatorcontrib>Sleijfer, Stefan</creatorcontrib><creatorcontrib>Van der Veldt, Astrid A. M.</creatorcontrib><creatorcontrib>Debets, Reno</creatorcontrib><creatorcontrib>Van Schaik, Ron H. N.</creatorcontrib><creatorcontrib>Aerts, Joachim G. J. V.</creatorcontrib><creatorcontrib>Mathijssen, Ron H. J.</creatorcontrib><title>Granzyme B is correlated with clinical outcome after PD-1 blockade in patients with stage IV non-small-cell lung cancer</title><title>Journal for immunotherapy of cancer</title><addtitle>J Immunother Cancer</addtitle><addtitle>J IMMUNOTHER CANCER</addtitle><addtitle>J Immunother Cancer</addtitle><description>BackgroundA minority of patients with advanced non-small-cell lung cancer (NSCLC) benefit from treatment with immune checkpoint inhibitors (ICIs). Ineffective effector function of activated T and NK cells may lead to reduced tumor cell death, even when these activated effector cells are released from their immune checkpoint brake. Hence, in this study we aimed to assess the association of baseline serum granzyme B, as well as germline variation of the GZMB gene, with clinical outcome to programmed cell death protein 1 (PD-1) blockade.MethodsA total of 347 patients with stage IV NSCLC who started nivolumab treatment between June 2013 and June 2017 were prospectively included. Baseline serum and whole blood was available, allowing for protein quantification and targeted DNA sequencing. Clinical outcome was based on best overall response (BOR) according to Response Evaluation Criteria in Solid Tumors, V.1.1, progression-free survival (PFS), and overall survival (OS).ResultsPatients with low serum levels of granzyme B had worse PFS (HR: 1.96; 95% CI: 1.12 to 3.43; p=0.018) and worse OS (HR: 2.08; 95% CI: 1.12 to 3.87; p=0.021) than patients with high baseline serum levels. To validate the findings, germline variation of GZMB rs8192917 was assessed. Patients with homozygous and heterozygous variants of GZMB rs8192917 had worse BOR (OR: 1.60; 95% CI: 1.01 to 2.52; p=0.044) and worse PFS (HR: 1.38; 95% CI:1.02 to 1.87; p=0.036) than wild types.ConclusionsA low baseline serum level of granzyme B and germline variation of GZMB was associated with worse clinical outcome in NSCLC, emphasizing the relevance and additional value of monitoring germline genetic variations which mirror cytotoxic functions of T cells in ICI therapy.Trail registration numberDutch Trial Registry (NL6828).</description><subject>Apoptosis</subject><subject>Cancer</subject><subject>Cell death</subject><subject>Clinical outcomes</subject><subject>Clinical/Translational Cancer Immunotherapy</subject><subject>Disease</subject><subject>Flow cytometry</subject><subject>genetic markers</subject><subject>Immunology</subject><subject>Immunotherapy</subject><subject>Life Sciences & Biomedicine</subject><subject>Lung cancer</subject><subject>lung neoplasms</subject><subject>Lymphocytes</subject><subject>Oncology</subject><subject>Patients</subject><subject>programmed cell death 1 receptor</subject><subject>Proteins</subject><subject>Regression analysis</subject><subject>Science & Technology</subject><subject>T cell receptors</subject><subject>translational medical research</subject><issn>2051-1426</issn><issn>2051-1426</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2020</creationdate><recordtype>article</recordtype><sourceid>9YT</sourceid><sourceid>ACMMV</sourceid><sourceid>AOWDO</sourceid><sourceid>BENPR</sourceid><sourceid>DOA</sourceid><recordid>eNqNks1rFDEYxgdRbKm9e5KAF0FHk8wkk7kIumpdKOhBvYYk884260yyJhmX-tebceq2FYSeEpLf8_B-PEXxmOCXhFT81dYmU1JMcYkxZoLfK44pZqQkNeX3b9yPitMYt5khuKqEEA-Lo4rWnFS1OC72Z0G5X5cjoLfIRmR8CDCoBB3a23SBzGCdNWpAfkrGZ0r1CQL6_K4kSA_efFcdIOvQTiULLsVFFZPaAFp_Q867Mo5qGEoDw4CGyW2QUc5AeFQ86NUQ4fTqPCm-fnj_ZfWxPP90tl69OS8141UqG6U0UOgbJmqOKVECqo6LRre00Z1WugJBue4UrnAnelObPBDVE9Ea3BHCqpNivfh2Xm3lLthRhUvplZV_HnzYSBWSNQNIQcCQlra6V7o2hinBgWDgHOuKNo3IXq8Xr92kR-hMbjio4Zbp7R9nL-TG_5QNZTVhdTZ4dmUQ_I8JYpKjjfNklAM_RUlrnBultJ3rfvoPuvVTcHlUkjJGW9FQ2mQKL5QJPsYA_aEYguUcEjmHRM4hkUtIsuTJzSYOgr-RyIBYgD1o30eT92rggM0unBLcsjlQbGVT3rx3Kz-5lKXP7y69pvW4vUvdL67pwyz-i_8G_v_0Vg</recordid><startdate>202005</startdate><enddate>202005</enddate><creator>Hurkmans, Daan P.</creator><creator>Basak, Edwin A.</creator><creator>Schepers, Nina</creator><creator>Oomen-De Hoop, Esther</creator><creator>Van der Leest, Cor H.</creator><creator>El Bouazzaoui, Samira</creator><creator>Bins, Sander</creator><creator>Koolen, Stijn L. W.</creator><creator>Sleijfer, Stefan</creator><creator>Van der Veldt, Astrid A. M.</creator><creator>Debets, Reno</creator><creator>Van Schaik, Ron H. N.</creator><creator>Aerts, Joachim G. J. V.</creator><creator>Mathijssen, Ron H. J.</creator><general>BMJ Publishing Group Ltd</general><general>Bmj Publishing Group</general><general>BMJ Publishing Group LTD</general><general>BMJ Publishing Group</general><scope>9YT</scope><scope>ACMMV</scope><scope>AOWDO</scope><scope>BLEPL</scope><scope>DTL</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BENPR</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>K9.</scope><scope>M0S</scope><scope>M1P</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>7X8</scope><scope>5PM</scope><scope>DOA</scope><orcidid>https://orcid.org/0000-0002-8750-5188</orcidid><orcidid>https://orcid.org/0000-0002-0973-7530</orcidid></search><sort><creationdate>202005</creationdate><title>Granzyme B is correlated with clinical outcome after PD-1 blockade in patients with stage IV non-small-cell lung cancer</title><author>Hurkmans, Daan P. ; Basak, Edwin A. ; Schepers, Nina ; Oomen-De Hoop, Esther ; Van der Leest, Cor H. ; El Bouazzaoui, Samira ; Bins, Sander ; Koolen, Stijn L. W. ; Sleijfer, Stefan ; Van der Veldt, Astrid A. M. ; Debets, Reno ; Van Schaik, Ron H. N. ; Aerts, Joachim G. J. V. ; Mathijssen, Ron H. J.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-b563t-7aabe2ef75846021a8e3d687b927bdbab3e826bda030d8fc4c202af189c0d1153</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2020</creationdate><topic>Apoptosis</topic><topic>Cancer</topic><topic>Cell death</topic><topic>Clinical outcomes</topic><topic>Clinical/Translational Cancer Immunotherapy</topic><topic>Disease</topic><topic>Flow cytometry</topic><topic>genetic markers</topic><topic>Immunology</topic><topic>Immunotherapy</topic><topic>Life Sciences & Biomedicine</topic><topic>Lung cancer</topic><topic>lung neoplasms</topic><topic>Lymphocytes</topic><topic>Oncology</topic><topic>Patients</topic><topic>programmed cell death 1 receptor</topic><topic>Proteins</topic><topic>Regression analysis</topic><topic>Science & Technology</topic><topic>T cell receptors</topic><topic>translational medical research</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Hurkmans, Daan P.</creatorcontrib><creatorcontrib>Basak, Edwin A.</creatorcontrib><creatorcontrib>Schepers, Nina</creatorcontrib><creatorcontrib>Oomen-De Hoop, Esther</creatorcontrib><creatorcontrib>Van der Leest, Cor H.</creatorcontrib><creatorcontrib>El Bouazzaoui, Samira</creatorcontrib><creatorcontrib>Bins, Sander</creatorcontrib><creatorcontrib>Koolen, Stijn L. W.</creatorcontrib><creatorcontrib>Sleijfer, Stefan</creatorcontrib><creatorcontrib>Van der Veldt, Astrid A. M.</creatorcontrib><creatorcontrib>Debets, Reno</creatorcontrib><creatorcontrib>Van Schaik, Ron H. N.</creatorcontrib><creatorcontrib>Aerts, Joachim G. J. V.</creatorcontrib><creatorcontrib>Mathijssen, Ron H. J.</creatorcontrib><collection>BMJ Open Access Journals</collection><collection>BMJ Journals:Open Access</collection><collection>Web of Science - Science Citation Index Expanded - 2020</collection><collection>Web of Science Core Collection</collection><collection>Science Citation Index Expanded</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>ProQuest Central</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Publicly Available Content Database</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>Journal for immunotherapy of cancer</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Hurkmans, Daan P.</au><au>Basak, Edwin A.</au><au>Schepers, Nina</au><au>Oomen-De Hoop, Esther</au><au>Van der Leest, Cor H.</au><au>El Bouazzaoui, Samira</au><au>Bins, Sander</au><au>Koolen, Stijn L. W.</au><au>Sleijfer, Stefan</au><au>Van der Veldt, Astrid A. M.</au><au>Debets, Reno</au><au>Van Schaik, Ron H. N.</au><au>Aerts, Joachim G. J. V.</au><au>Mathijssen, Ron H. J.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Granzyme B is correlated with clinical outcome after PD-1 blockade in patients with stage IV non-small-cell lung cancer</atitle><jtitle>Journal for immunotherapy of cancer</jtitle><stitle>J Immunother Cancer</stitle><stitle>J IMMUNOTHER CANCER</stitle><addtitle>J Immunother Cancer</addtitle><date>2020-05</date><risdate>2020</risdate><volume>8</volume><issue>1</issue><spage>e000586</spage><pages>e000586-</pages><artnum>000586</artnum><issn>2051-1426</issn><eissn>2051-1426</eissn><abstract>BackgroundA minority of patients with advanced non-small-cell lung cancer (NSCLC) benefit from treatment with immune checkpoint inhibitors (ICIs). Ineffective effector function of activated T and NK cells may lead to reduced tumor cell death, even when these activated effector cells are released from their immune checkpoint brake. Hence, in this study we aimed to assess the association of baseline serum granzyme B, as well as germline variation of the GZMB gene, with clinical outcome to programmed cell death protein 1 (PD-1) blockade.MethodsA total of 347 patients with stage IV NSCLC who started nivolumab treatment between June 2013 and June 2017 were prospectively included. Baseline serum and whole blood was available, allowing for protein quantification and targeted DNA sequencing. Clinical outcome was based on best overall response (BOR) according to Response Evaluation Criteria in Solid Tumors, V.1.1, progression-free survival (PFS), and overall survival (OS).ResultsPatients with low serum levels of granzyme B had worse PFS (HR: 1.96; 95% CI: 1.12 to 3.43; p=0.018) and worse OS (HR: 2.08; 95% CI: 1.12 to 3.87; p=0.021) than patients with high baseline serum levels. To validate the findings, germline variation of GZMB rs8192917 was assessed. Patients with homozygous and heterozygous variants of GZMB rs8192917 had worse BOR (OR: 1.60; 95% CI: 1.01 to 2.52; p=0.044) and worse PFS (HR: 1.38; 95% CI:1.02 to 1.87; p=0.036) than wild types.ConclusionsA low baseline serum level of granzyme B and germline variation of GZMB was associated with worse clinical outcome in NSCLC, emphasizing the relevance and additional value of monitoring germline genetic variations which mirror cytotoxic functions of T cells in ICI therapy.Trail registration numberDutch Trial Registry (NL6828).</abstract><cop>LONDON</cop><pub>BMJ Publishing Group Ltd</pub><pmid>32461348</pmid><doi>10.1136/jitc-2020-000586</doi><tpages>9</tpages><orcidid>https://orcid.org/0000-0002-8750-5188</orcidid><orcidid>https://orcid.org/0000-0002-0973-7530</orcidid><oa>free_for_read</oa></addata></record> |
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| subjects | Apoptosis Cancer Cell death Clinical outcomes Clinical/Translational Cancer Immunotherapy Disease Flow cytometry genetic markers Immunology Immunotherapy Life Sciences & Biomedicine Lung cancer lung neoplasms Lymphocytes Oncology Patients programmed cell death 1 receptor Proteins Regression analysis Science & Technology T cell receptors translational medical research |
| title | Granzyme B is correlated with clinical outcome after PD-1 blockade in patients with stage IV non-small-cell lung cancer |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-27T08%3A07%3A23IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_webof&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Granzyme%20B%20is%20correlated%20with%20clinical%20outcome%20after%20PD-1%20blockade%20in%20patients%20with%20stage%20IV%20non-small-cell%20lung%20cancer&rft.jtitle=Journal%20for%20immunotherapy%20of%20cancer&rft.au=Hurkmans,%20Daan%20P.&rft.date=2020-05&rft.volume=8&rft.issue=1&rft.spage=e000586&rft.pages=e000586-&rft.artnum=000586&rft.issn=2051-1426&rft.eissn=2051-1426&rft_id=info:doi/10.1136/jitc-2020-000586&rft_dat=%3Cproquest_webof%3E2552987227%3C/proquest_webof%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2552987227&rft_id=info:pmid/32461348&rft_doaj_id=oai_doaj_org_article_81ec1929bfab4cc5a86e10e660b32778&rfr_iscdi=true |