High systemic and tumor-associated IL-8 correlates with reduced clinical benefit of PD-L1 blockade
Although elevated plasma interleukin-8 (pIL-8) has been associated with poor outcome to immune checkpoint blockade 1 , this has not been comprehensively evaluated in large randomized studies. Here we analyzed circulating pIL-8 and IL8 gene expression in peripheral blood mononuclear cells and tumors...
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| Veröffentlicht in: | Nature medicine 2020-05, Vol.26 (5), p.693-698 |
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| creator | Yuen, Kobe C. Liu, Li-Fen Gupta, Vinita Madireddi, Shravan Keerthivasan, Shilpa Li, Congfen Rishipathak, Deepali Williams, Patrick Kadel, Edward E. Koeppen, Hartmut Chen, Ying-Jiun Modrusan, Zora Grogan, Jane L. Banchereau, Romain Leng, Ning Thastrom, AnnChristine Shen, Xiadong Hashimoto, Kenji Tayama, Darren van der Heijden, Michiel S. Rosenberg, Jonathan E. McDermott, David F. Powles, Thomas Hegde, Priti S. Huseni, Mahrukh A. Mariathasan, Sanjeev |
| description | Although elevated plasma interleukin-8 (pIL-8) has been associated with poor outcome to immune checkpoint blockade
1
, this has not been comprehensively evaluated in large randomized studies. Here we analyzed circulating pIL-8 and
IL8
gene expression in peripheral blood mononuclear cells and tumors of patients treated with atezolizumab (anti-PD-L1 monoclonal antibody) from multiple randomized trials representing 1,445 patients with metastatic urothelial carcinoma (mUC) and metastatic renal cell carcinoma. High levels of IL-8 in plasma, peripheral blood mononuclear cells and tumors were associated with decreased efficacy of atezolizumab in patients with mUC and metastatic renal cell carcinoma, even in tumors that were classically CD8
+
T cell inflamed. Low baseline pIL-8 in patients with mUC was associated with increased response to atezolizumab and chemotherapy. Patients with mUC who experienced on-treatment decreases in pIL-8 exhibited improved overall survival when treated with atezolizumab but not with chemotherapy. Single-cell RNA sequencing of the immune compartment showed that
IL8
is primarily expressed in circulating and intratumoral myeloid cells and that high
IL8
expression is associated with downregulation of the antigen-presentation machinery. Therapies that can reverse the impacts of IL-8-mediated myeloid inflammation will be essential for improving outcomes of patients treated with immune checkpoint inhibitors.
In a retrospective analysis of data from three clinical trials, increased baseline peripheral and tumor IL-8 levels were associated with worse clinical outcomes in patients with metastatic urothelial carcinoma and metastatic renal cell carcinoma treated with anti-PD-L1 therapy. |
| doi_str_mv | 10.1038/s41591-020-0860-1 |
| format | Article |
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1
, this has not been comprehensively evaluated in large randomized studies. Here we analyzed circulating pIL-8 and
IL8
gene expression in peripheral blood mononuclear cells and tumors of patients treated with atezolizumab (anti-PD-L1 monoclonal antibody) from multiple randomized trials representing 1,445 patients with metastatic urothelial carcinoma (mUC) and metastatic renal cell carcinoma. High levels of IL-8 in plasma, peripheral blood mononuclear cells and tumors were associated with decreased efficacy of atezolizumab in patients with mUC and metastatic renal cell carcinoma, even in tumors that were classically CD8
+
T cell inflamed. Low baseline pIL-8 in patients with mUC was associated with increased response to atezolizumab and chemotherapy. Patients with mUC who experienced on-treatment decreases in pIL-8 exhibited improved overall survival when treated with atezolizumab but not with chemotherapy. Single-cell RNA sequencing of the immune compartment showed that
IL8
is primarily expressed in circulating and intratumoral myeloid cells and that high
IL8
expression is associated with downregulation of the antigen-presentation machinery. Therapies that can reverse the impacts of IL-8-mediated myeloid inflammation will be essential for improving outcomes of patients treated with immune checkpoint inhibitors.
In a retrospective analysis of data from three clinical trials, increased baseline peripheral and tumor IL-8 levels were associated with worse clinical outcomes in patients with metastatic urothelial carcinoma and metastatic renal cell carcinoma treated with anti-PD-L1 therapy.</description><identifier>ISSN: 1078-8956</identifier><identifier>EISSN: 1546-170X</identifier><identifier>DOI: 10.1038/s41591-020-0860-1</identifier><identifier>PMID: 32405063</identifier><language>eng</language><publisher>New York: Nature Publishing Group US</publisher><subject>692/53 ; 692/699/67/1059/2325 ; 692/699/67/327 ; 692/699/67/589/1336 ; 692/699/67/589/1588/1351 ; Adult ; Antibodies, Monoclonal, Humanized - therapeutic use ; Antigen presentation ; Antigens ; Antineoplastic Agents, Immunological - therapeutic use ; Apoptotic proteins ; B7-H1 Antigen - antagonists & inhibitors ; B7-H1 Antigen - immunology ; Biomarkers, Pharmacological - blood ; Biomarkers, Pharmacological - metabolism ; Biomarkers, Tumor - blood ; Biomarkers, Tumor - metabolism ; Biomedical and Life Sciences ; Biomedicine ; Bladder cancer ; Blood circulation ; Cancer Research ; Carcinoma, Renal cell ; Carcinoma, Renal Cell - diagnosis ; Carcinoma, Renal Cell - drug therapy ; Carcinoma, Renal Cell - metabolism ; Carcinoma, Renal Cell - mortality ; Carcinoma, Transitional Cell - diagnosis ; Carcinoma, Transitional Cell - drug therapy ; Carcinoma, Transitional Cell - metabolism ; Carcinoma, Transitional Cell - mortality ; CD8 antigen ; Chemotherapy ; Clinical trials ; Drug Resistance, Neoplasm ; Drug therapy ; Female ; Gene expression ; Gene sequencing ; Health aspects ; Humans ; Immune checkpoint inhibitors ; Infectious Diseases ; Inflammation ; Interleukin 8 ; Interleukin-8 - blood ; Interleukin-8 - metabolism ; Kidney cancer ; Kidney Neoplasms - diagnosis ; Kidney Neoplasms - drug therapy ; Kidney Neoplasms - metabolism ; Kidney Neoplasms - mortality ; Letter ; Leukocytes (mononuclear) ; Lymphocytes ; Lymphocytes T ; Male ; Metabolic Diseases ; Metastases ; Metastasis ; Molecular Medicine ; Monoclonal antibodies ; Myeloid cells ; Neoplasms - diagnosis ; Neoplasms - drug therapy ; Neoplasms - metabolism ; Neoplasms - mortality ; Neurosciences ; Patient outcomes ; Patients ; PD-L1 protein ; Peripheral blood mononuclear cells ; Prognosis ; Randomization ; Renal cell carcinoma ; Ribonucleic acid ; RNA ; Survival Analysis ; Targeted cancer therapy ; Treatment Failure ; Tumors ; Urologic Neoplasms - diagnosis ; Urologic Neoplasms - drug therapy ; Urologic Neoplasms - metabolism ; Urologic Neoplasms - mortality ; Urothelial carcinoma</subject><ispartof>Nature medicine, 2020-05, Vol.26 (5), p.693-698</ispartof><rights>The Author(s), under exclusive licence to Springer Nature America, Inc. 2020. corrected publication 2021</rights><rights>COPYRIGHT 2020 Nature Publishing Group</rights><rights>The Author(s), under exclusive licence to Springer Nature America, Inc. 2020.</rights><rights>The Author(s), under exclusive licence to Springer Nature America, Inc. 2020. corrected publication 2021.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c647t-86cb56fc56dd2f29aba008d171d76c1ab979584080289526b07b070c7b259e873</citedby><cites>FETCH-LOGICAL-c647t-86cb56fc56dd2f29aba008d171d76c1ab979584080289526b07b070c7b259e873</cites><orcidid>0000-0003-4062-7134 ; 0000-0002-2675-5095 ; 0000-0001-6916-6445 ; 0000-0001-5034-773X ; 0000-0003-3030-6628 ; 0000-0001-8166-3401</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1038/s41591-020-0860-1$$EPDF$$P50$$Gspringer$$H</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1038/s41591-020-0860-1$$EHTML$$P50$$Gspringer$$H</linktohtml><link.rule.ids>314,776,780,27901,27902,41464,42533,51294</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/32405063$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Yuen, Kobe C.</creatorcontrib><creatorcontrib>Liu, Li-Fen</creatorcontrib><creatorcontrib>Gupta, Vinita</creatorcontrib><creatorcontrib>Madireddi, Shravan</creatorcontrib><creatorcontrib>Keerthivasan, Shilpa</creatorcontrib><creatorcontrib>Li, Congfen</creatorcontrib><creatorcontrib>Rishipathak, Deepali</creatorcontrib><creatorcontrib>Williams, Patrick</creatorcontrib><creatorcontrib>Kadel, Edward E.</creatorcontrib><creatorcontrib>Koeppen, Hartmut</creatorcontrib><creatorcontrib>Chen, Ying-Jiun</creatorcontrib><creatorcontrib>Modrusan, Zora</creatorcontrib><creatorcontrib>Grogan, Jane L.</creatorcontrib><creatorcontrib>Banchereau, Romain</creatorcontrib><creatorcontrib>Leng, Ning</creatorcontrib><creatorcontrib>Thastrom, AnnChristine</creatorcontrib><creatorcontrib>Shen, Xiadong</creatorcontrib><creatorcontrib>Hashimoto, Kenji</creatorcontrib><creatorcontrib>Tayama, Darren</creatorcontrib><creatorcontrib>van der Heijden, Michiel S.</creatorcontrib><creatorcontrib>Rosenberg, Jonathan E.</creatorcontrib><creatorcontrib>McDermott, David F.</creatorcontrib><creatorcontrib>Powles, Thomas</creatorcontrib><creatorcontrib>Hegde, Priti S.</creatorcontrib><creatorcontrib>Huseni, Mahrukh A.</creatorcontrib><creatorcontrib>Mariathasan, Sanjeev</creatorcontrib><title>High systemic and tumor-associated IL-8 correlates with reduced clinical benefit of PD-L1 blockade</title><title>Nature medicine</title><addtitle>Nat Med</addtitle><addtitle>Nat Med</addtitle><description>Although elevated plasma interleukin-8 (pIL-8) has been associated with poor outcome to immune checkpoint blockade
1
, this has not been comprehensively evaluated in large randomized studies. Here we analyzed circulating pIL-8 and
IL8
gene expression in peripheral blood mononuclear cells and tumors of patients treated with atezolizumab (anti-PD-L1 monoclonal antibody) from multiple randomized trials representing 1,445 patients with metastatic urothelial carcinoma (mUC) and metastatic renal cell carcinoma. High levels of IL-8 in plasma, peripheral blood mononuclear cells and tumors were associated with decreased efficacy of atezolizumab in patients with mUC and metastatic renal cell carcinoma, even in tumors that were classically CD8
+
T cell inflamed. Low baseline pIL-8 in patients with mUC was associated with increased response to atezolizumab and chemotherapy. Patients with mUC who experienced on-treatment decreases in pIL-8 exhibited improved overall survival when treated with atezolizumab but not with chemotherapy. Single-cell RNA sequencing of the immune compartment showed that
IL8
is primarily expressed in circulating and intratumoral myeloid cells and that high
IL8
expression is associated with downregulation of the antigen-presentation machinery. Therapies that can reverse the impacts of IL-8-mediated myeloid inflammation will be essential for improving outcomes of patients treated with immune checkpoint inhibitors.
In a retrospective analysis of data from three clinical trials, increased baseline peripheral and tumor IL-8 levels were associated with worse clinical outcomes in patients with metastatic urothelial carcinoma and metastatic renal cell carcinoma treated with anti-PD-L1 therapy.</description><subject>692/53</subject><subject>692/699/67/1059/2325</subject><subject>692/699/67/327</subject><subject>692/699/67/589/1336</subject><subject>692/699/67/589/1588/1351</subject><subject>Adult</subject><subject>Antibodies, Monoclonal, Humanized - therapeutic use</subject><subject>Antigen presentation</subject><subject>Antigens</subject><subject>Antineoplastic Agents, Immunological - therapeutic use</subject><subject>Apoptotic proteins</subject><subject>B7-H1 Antigen - antagonists & inhibitors</subject><subject>B7-H1 Antigen - immunology</subject><subject>Biomarkers, Pharmacological - blood</subject><subject>Biomarkers, Pharmacological - metabolism</subject><subject>Biomarkers, Tumor - blood</subject><subject>Biomarkers, Tumor - metabolism</subject><subject>Biomedical and Life Sciences</subject><subject>Biomedicine</subject><subject>Bladder cancer</subject><subject>Blood circulation</subject><subject>Cancer Research</subject><subject>Carcinoma, Renal cell</subject><subject>Carcinoma, Renal Cell - diagnosis</subject><subject>Carcinoma, Renal Cell - drug therapy</subject><subject>Carcinoma, Renal Cell - metabolism</subject><subject>Carcinoma, Renal Cell - mortality</subject><subject>Carcinoma, Transitional Cell - diagnosis</subject><subject>Carcinoma, Transitional Cell - drug therapy</subject><subject>Carcinoma, Transitional Cell - metabolism</subject><subject>Carcinoma, Transitional Cell - mortality</subject><subject>CD8 antigen</subject><subject>Chemotherapy</subject><subject>Clinical trials</subject><subject>Drug Resistance, Neoplasm</subject><subject>Drug therapy</subject><subject>Female</subject><subject>Gene expression</subject><subject>Gene sequencing</subject><subject>Health aspects</subject><subject>Humans</subject><subject>Immune checkpoint inhibitors</subject><subject>Infectious Diseases</subject><subject>Inflammation</subject><subject>Interleukin 8</subject><subject>Interleukin-8 - blood</subject><subject>Interleukin-8 - metabolism</subject><subject>Kidney cancer</subject><subject>Kidney Neoplasms - diagnosis</subject><subject>Kidney Neoplasms - drug therapy</subject><subject>Kidney Neoplasms - metabolism</subject><subject>Kidney Neoplasms - mortality</subject><subject>Letter</subject><subject>Leukocytes (mononuclear)</subject><subject>Lymphocytes</subject><subject>Lymphocytes T</subject><subject>Male</subject><subject>Metabolic Diseases</subject><subject>Metastases</subject><subject>Metastasis</subject><subject>Molecular Medicine</subject><subject>Monoclonal antibodies</subject><subject>Myeloid cells</subject><subject>Neoplasms - diagnosis</subject><subject>Neoplasms - drug therapy</subject><subject>Neoplasms - metabolism</subject><subject>Neoplasms - mortality</subject><subject>Neurosciences</subject><subject>Patient outcomes</subject><subject>Patients</subject><subject>PD-L1 protein</subject><subject>Peripheral blood mononuclear cells</subject><subject>Prognosis</subject><subject>Randomization</subject><subject>Renal cell carcinoma</subject><subject>Ribonucleic acid</subject><subject>RNA</subject><subject>Survival Analysis</subject><subject>Targeted cancer therapy</subject><subject>Treatment Failure</subject><subject>Tumors</subject><subject>Urologic Neoplasms - diagnosis</subject><subject>Urologic Neoplasms - drug therapy</subject><subject>Urologic Neoplasms - metabolism</subject><subject>Urologic Neoplasms - mortality</subject><subject>Urothelial carcinoma</subject><issn>1078-8956</issn><issn>1546-170X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2020</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>8G5</sourceid><sourceid>BENPR</sourceid><sourceid>GUQSH</sourceid><sourceid>M2O</sourceid><recordid>eNqN0luL1DAUAOAiiruu_gBfJCCIPmQ9Sds0fVzWyw4MrHjDt5Cm6UzWTLObpOj-e0-Z1XVkFGmgbfKdXE5OUTxmcMyglC9TxeqWUeBAQQqg7E5xyOpKUNbAl7v4DY2ksq3FQfEgpQsAKKFu7xcHJa-gBlEeFt2ZW61Juk7ZbpwheuxJnjYhUp1SME5n25PFkkpiQozW438i31xek2j7yeCg8W50RnvS2dEOLpMwkHev6JKRzgfzVff2YXFv0D7ZRzfvo-LTm9cfT8_o8vzt4vRkSY2omkylMF0tBlOLvucDb3WnAWTPGtY3wjDdtU1bywokcDwSFx002MA0Ha9bK5vyqHi-nfcyhqvJpqw2LhnrvR5tmJLCM5fA27qpkD79g16EKY64O1RSCA64zr8V8FKKiotbtdLeKjcOIUdt5qXViUCEu-McFd2jVpizqH2YM4fdO_54j8enn-9pb8CLnQA02X7PKz2lpBYf3v-_Pf-8a5_9ZtdW-7xOwU_ZhTHtQraFJoaUoh3UZXQbHa8VAzWXq9qWq8JyVXO5KoYxT24yPHUb2_-K-FmfCPgWJBwaVzbeXsHfZ_0BIZ7tAg</recordid><startdate>20200501</startdate><enddate>20200501</enddate><creator>Yuen, Kobe 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systemic and tumor-associated IL-8 correlates with reduced clinical benefit of PD-L1 blockade</title><author>Yuen, Kobe C. ; Liu, Li-Fen ; Gupta, Vinita ; Madireddi, Shravan ; Keerthivasan, Shilpa ; Li, Congfen ; Rishipathak, Deepali ; Williams, Patrick ; Kadel, Edward E. ; Koeppen, Hartmut ; Chen, Ying-Jiun ; Modrusan, Zora ; Grogan, Jane L. ; Banchereau, Romain ; Leng, Ning ; Thastrom, AnnChristine ; Shen, Xiadong ; Hashimoto, Kenji ; Tayama, Darren ; van der Heijden, Michiel S. ; Rosenberg, Jonathan E. ; McDermott, David F. ; Powles, Thomas ; Hegde, Priti S. ; Huseni, Mahrukh A. ; Mariathasan, Sanjeev</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c647t-86cb56fc56dd2f29aba008d171d76c1ab979584080289526b07b070c7b259e873</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2020</creationdate><topic>692/53</topic><topic>692/699/67/1059/2325</topic><topic>692/699/67/327</topic><topic>692/699/67/589/1336</topic><topic>692/699/67/589/1588/1351</topic><topic>Adult</topic><topic>Antibodies, Monoclonal, Humanized - therapeutic use</topic><topic>Antigen presentation</topic><topic>Antigens</topic><topic>Antineoplastic Agents, Immunological - therapeutic use</topic><topic>Apoptotic proteins</topic><topic>B7-H1 Antigen - antagonists & inhibitors</topic><topic>B7-H1 Antigen - immunology</topic><topic>Biomarkers, Pharmacological - blood</topic><topic>Biomarkers, Pharmacological - metabolism</topic><topic>Biomarkers, Tumor - blood</topic><topic>Biomarkers, Tumor - metabolism</topic><topic>Biomedical and Life Sciences</topic><topic>Biomedicine</topic><topic>Bladder cancer</topic><topic>Blood circulation</topic><topic>Cancer Research</topic><topic>Carcinoma, Renal cell</topic><topic>Carcinoma, Renal Cell - diagnosis</topic><topic>Carcinoma, Renal Cell - drug therapy</topic><topic>Carcinoma, Renal Cell - metabolism</topic><topic>Carcinoma, Renal Cell - mortality</topic><topic>Carcinoma, Transitional Cell - diagnosis</topic><topic>Carcinoma, Transitional Cell - drug therapy</topic><topic>Carcinoma, Transitional Cell - metabolism</topic><topic>Carcinoma, Transitional Cell - mortality</topic><topic>CD8 antigen</topic><topic>Chemotherapy</topic><topic>Clinical trials</topic><topic>Drug Resistance, Neoplasm</topic><topic>Drug therapy</topic><topic>Female</topic><topic>Gene expression</topic><topic>Gene sequencing</topic><topic>Health aspects</topic><topic>Humans</topic><topic>Immune checkpoint inhibitors</topic><topic>Infectious Diseases</topic><topic>Inflammation</topic><topic>Interleukin 8</topic><topic>Interleukin-8 - blood</topic><topic>Interleukin-8 - metabolism</topic><topic>Kidney cancer</topic><topic>Kidney Neoplasms - diagnosis</topic><topic>Kidney Neoplasms - drug therapy</topic><topic>Kidney Neoplasms - metabolism</topic><topic>Kidney Neoplasms - mortality</topic><topic>Letter</topic><topic>Leukocytes (mononuclear)</topic><topic>Lymphocytes</topic><topic>Lymphocytes T</topic><topic>Male</topic><topic>Metabolic Diseases</topic><topic>Metastases</topic><topic>Metastasis</topic><topic>Molecular Medicine</topic><topic>Monoclonal antibodies</topic><topic>Myeloid cells</topic><topic>Neoplasms - diagnosis</topic><topic>Neoplasms - drug therapy</topic><topic>Neoplasms - metabolism</topic><topic>Neoplasms - mortality</topic><topic>Neurosciences</topic><topic>Patient outcomes</topic><topic>Patients</topic><topic>PD-L1 protein</topic><topic>Peripheral blood mononuclear cells</topic><topic>Prognosis</topic><topic>Randomization</topic><topic>Renal cell carcinoma</topic><topic>Ribonucleic acid</topic><topic>RNA</topic><topic>Survival Analysis</topic><topic>Targeted cancer therapy</topic><topic>Treatment Failure</topic><topic>Tumors</topic><topic>Urologic Neoplasms - diagnosis</topic><topic>Urologic Neoplasms - drug therapy</topic><topic>Urologic Neoplasms - metabolism</topic><topic>Urologic Neoplasms - mortality</topic><topic>Urothelial carcinoma</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Yuen, Kobe C.</creatorcontrib><creatorcontrib>Liu, Li-Fen</creatorcontrib><creatorcontrib>Gupta, Vinita</creatorcontrib><creatorcontrib>Madireddi, Shravan</creatorcontrib><creatorcontrib>Keerthivasan, Shilpa</creatorcontrib><creatorcontrib>Li, Congfen</creatorcontrib><creatorcontrib>Rishipathak, Deepali</creatorcontrib><creatorcontrib>Williams, Patrick</creatorcontrib><creatorcontrib>Kadel, Edward E.</creatorcontrib><creatorcontrib>Koeppen, Hartmut</creatorcontrib><creatorcontrib>Chen, Ying-Jiun</creatorcontrib><creatorcontrib>Modrusan, Zora</creatorcontrib><creatorcontrib>Grogan, Jane L.</creatorcontrib><creatorcontrib>Banchereau, Romain</creatorcontrib><creatorcontrib>Leng, Ning</creatorcontrib><creatorcontrib>Thastrom, AnnChristine</creatorcontrib><creatorcontrib>Shen, Xiadong</creatorcontrib><creatorcontrib>Hashimoto, Kenji</creatorcontrib><creatorcontrib>Tayama, Darren</creatorcontrib><creatorcontrib>van der Heijden, Michiel S.</creatorcontrib><creatorcontrib>Rosenberg, Jonathan E.</creatorcontrib><creatorcontrib>McDermott, David F.</creatorcontrib><creatorcontrib>Powles, Thomas</creatorcontrib><creatorcontrib>Hegde, Priti S.</creatorcontrib><creatorcontrib>Huseni, Mahrukh A.</creatorcontrib><creatorcontrib>Mariathasan, Sanjeev</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Gale In Context: Opposing Viewpoints</collection><collection>Gale In Context: Science</collection><collection>ProQuest Central (Corporate)</collection><collection>Animal Behavior Abstracts</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Chemoreception Abstracts</collection><collection>Immunology Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>Toxicology Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Biology Database (Alumni Edition)</collection><collection>Medical Database (Alumni Edition)</collection><collection>Science Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Technology Research Database</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>Research Library (Alumni Edition)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest One Sustainability</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Natural Science Collection</collection><collection>Environmental Sciences and Pollution Management</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Engineering Research Database</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>Research Library Prep</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>ProQuest Biological Science Collection</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Research Library</collection><collection>Science Database</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Biological Science Database</collection><collection>Research Library (Corporate)</collection><collection>Biotechnology and BioEngineering Abstracts</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 Basic</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>Nature medicine</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Yuen, Kobe C.</au><au>Liu, Li-Fen</au><au>Gupta, Vinita</au><au>Madireddi, Shravan</au><au>Keerthivasan, Shilpa</au><au>Li, Congfen</au><au>Rishipathak, Deepali</au><au>Williams, Patrick</au><au>Kadel, Edward E.</au><au>Koeppen, Hartmut</au><au>Chen, Ying-Jiun</au><au>Modrusan, Zora</au><au>Grogan, Jane L.</au><au>Banchereau, Romain</au><au>Leng, Ning</au><au>Thastrom, AnnChristine</au><au>Shen, Xiadong</au><au>Hashimoto, Kenji</au><au>Tayama, Darren</au><au>van der Heijden, Michiel S.</au><au>Rosenberg, Jonathan E.</au><au>McDermott, David F.</au><au>Powles, Thomas</au><au>Hegde, Priti S.</au><au>Huseni, Mahrukh A.</au><au>Mariathasan, Sanjeev</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>High systemic and tumor-associated IL-8 correlates with reduced clinical benefit of PD-L1 blockade</atitle><jtitle>Nature medicine</jtitle><stitle>Nat Med</stitle><addtitle>Nat Med</addtitle><date>2020-05-01</date><risdate>2020</risdate><volume>26</volume><issue>5</issue><spage>693</spage><epage>698</epage><pages>693-698</pages><issn>1078-8956</issn><eissn>1546-170X</eissn><abstract>Although elevated plasma interleukin-8 (pIL-8) has been associated with poor outcome to immune checkpoint blockade
1
, this has not been comprehensively evaluated in large randomized studies. Here we analyzed circulating pIL-8 and
IL8
gene expression in peripheral blood mononuclear cells and tumors of patients treated with atezolizumab (anti-PD-L1 monoclonal antibody) from multiple randomized trials representing 1,445 patients with metastatic urothelial carcinoma (mUC) and metastatic renal cell carcinoma. High levels of IL-8 in plasma, peripheral blood mononuclear cells and tumors were associated with decreased efficacy of atezolizumab in patients with mUC and metastatic renal cell carcinoma, even in tumors that were classically CD8
+
T cell inflamed. Low baseline pIL-8 in patients with mUC was associated with increased response to atezolizumab and chemotherapy. Patients with mUC who experienced on-treatment decreases in pIL-8 exhibited improved overall survival when treated with atezolizumab but not with chemotherapy. Single-cell RNA sequencing of the immune compartment showed that
IL8
is primarily expressed in circulating and intratumoral myeloid cells and that high
IL8
expression is associated with downregulation of the antigen-presentation machinery. Therapies that can reverse the impacts of IL-8-mediated myeloid inflammation will be essential for improving outcomes of patients treated with immune checkpoint inhibitors.
In a retrospective analysis of data from three clinical trials, increased baseline peripheral and tumor IL-8 levels were associated with worse clinical outcomes in patients with metastatic urothelial carcinoma and metastatic renal cell carcinoma treated with anti-PD-L1 therapy.</abstract><cop>New York</cop><pub>Nature Publishing Group US</pub><pmid>32405063</pmid><doi>10.1038/s41591-020-0860-1</doi><tpages>6</tpages><orcidid>https://orcid.org/0000-0003-4062-7134</orcidid><orcidid>https://orcid.org/0000-0002-2675-5095</orcidid><orcidid>https://orcid.org/0000-0001-6916-6445</orcidid><orcidid>https://orcid.org/0000-0001-5034-773X</orcidid><orcidid>https://orcid.org/0000-0003-3030-6628</orcidid><orcidid>https://orcid.org/0000-0001-8166-3401</orcidid><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1078-8956 |
| ispartof | Nature medicine, 2020-05, Vol.26 (5), p.693-698 |
| issn | 1078-8956 1546-170X |
| language | eng |
| recordid | cdi_proquest_miscellaneous_2403029574 |
| source | MEDLINE; SpringerLink Journals; Nature Journals Online |
| subjects | 692/53 692/699/67/1059/2325 692/699/67/327 692/699/67/589/1336 692/699/67/589/1588/1351 Adult Antibodies, Monoclonal, Humanized - therapeutic use Antigen presentation Antigens Antineoplastic Agents, Immunological - therapeutic use Apoptotic proteins B7-H1 Antigen - antagonists & inhibitors B7-H1 Antigen - immunology Biomarkers, Pharmacological - blood Biomarkers, Pharmacological - metabolism Biomarkers, Tumor - blood Biomarkers, Tumor - metabolism Biomedical and Life Sciences Biomedicine Bladder cancer Blood circulation Cancer Research Carcinoma, Renal cell Carcinoma, Renal Cell - diagnosis Carcinoma, Renal Cell - drug therapy Carcinoma, Renal Cell - metabolism Carcinoma, Renal Cell - mortality Carcinoma, Transitional Cell - diagnosis Carcinoma, Transitional Cell - drug therapy Carcinoma, Transitional Cell - metabolism Carcinoma, Transitional Cell - mortality CD8 antigen Chemotherapy Clinical trials Drug Resistance, Neoplasm Drug therapy Female Gene expression Gene sequencing Health aspects Humans Immune checkpoint inhibitors Infectious Diseases Inflammation Interleukin 8 Interleukin-8 - blood Interleukin-8 - metabolism Kidney cancer Kidney Neoplasms - diagnosis Kidney Neoplasms - drug therapy Kidney Neoplasms - metabolism Kidney Neoplasms - mortality Letter Leukocytes (mononuclear) Lymphocytes Lymphocytes T Male Metabolic Diseases Metastases Metastasis Molecular Medicine Monoclonal antibodies Myeloid cells Neoplasms - diagnosis Neoplasms - drug therapy Neoplasms - metabolism Neoplasms - mortality Neurosciences Patient outcomes Patients PD-L1 protein Peripheral blood mononuclear cells Prognosis Randomization Renal cell carcinoma Ribonucleic acid RNA Survival Analysis Targeted cancer therapy Treatment Failure Tumors Urologic Neoplasms - diagnosis Urologic Neoplasms - drug therapy Urologic Neoplasms - metabolism Urologic Neoplasms - mortality Urothelial carcinoma |
| title | High systemic and tumor-associated IL-8 correlates with reduced clinical benefit of PD-L1 blockade |
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