DC-HIL/Gpnmb Is a Negative Regulator of Tumor Response to Immune Checkpoint Inhibitors
Immune checkpoint inhibitors (ICI) benefit only a minority of treated patients with cancer. Identification of biomarkers distinguishing responders and nonresponders will improve management of patients with cancer. Because the DC-HIL checkpoint differs from the PD1 pathway in expression and inhibitor...
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| Veröffentlicht in: | Clinical cancer research 2020-03, Vol.26 (6), p.1449-1459 |
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| creator | Chung, Jin-Sung Ramani, Vijay Kobayashi, Masato Fattah, Farjana Popat, Vinita Zhang, Song Cruz, Jr, Ponciano D Gerber, David E Ariizumi, Kiyoshi |
| description | Immune checkpoint inhibitors (ICI) benefit only a minority of treated patients with cancer. Identification of biomarkers distinguishing responders and nonresponders will improve management of patients with cancer. Because the DC-HIL checkpoint differs from the PD1 pathway in expression and inhibitory mechanisms, we examined whether DC-HIL expression regulates ICI responsiveness.
Plasma samples were collected from patients with advanced non-small cell lung carcinoma (NSCLC) (
= 76) at baseline and/or follow-up after ICI monotherapy. Blood-soluble DC-HIL (sDC-HIL) was determined and analyzed for correlation with the early tumor response. To study the mechanisms, we measured effect of anti-DC-HIL versus anti-PDL1 mAb on growth of mouse tumor cells in experimentally metastatic lung. Influence of DC-HIL to anti-PDL1 treatment was assessed by changes in tumor response after deletion of host-
gene, injection of DC-HIL-expressing myeloid-derived suppressor cells (MDSC), or induction of sDC-HIL expression.
Nonresponders expressed significantly higher levels of baseline sDC-HIL levels than responders. Among patients (
= 28) for fluctuation with time, nonresponders (14/15 cases) showed increasing or persistently elevated levels. Responders (12/13) had decreasing or persistently low levels. Among various tumors, B16 melanoma exhibited resistance to anti-PDL1 but responded to anti-DC-HIL mAb. Using B16 melanoma and LL2 lung cancer, we showed that deletion of host-derived DC-HIL expression converted the resistant tumor to one responsive to anti-PDL1 mAb. The responsive state was reversed by infusion of DC-HIL
MDSC or induction of sDC-HIL expression.
sDC-HIL in the blood and probably DC-HIL receptor expressed by MDSC play an important role in regulating response to ICI in advanced NSCLC. |
| doi_str_mv | 10.1158/1078-0432.CCR-19-2360 |
| format | Article |
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Plasma samples were collected from patients with advanced non-small cell lung carcinoma (NSCLC) (
= 76) at baseline and/or follow-up after ICI monotherapy. Blood-soluble DC-HIL (sDC-HIL) was determined and analyzed for correlation with the early tumor response. To study the mechanisms, we measured effect of anti-DC-HIL versus anti-PDL1 mAb on growth of mouse tumor cells in experimentally metastatic lung. Influence of DC-HIL to anti-PDL1 treatment was assessed by changes in tumor response after deletion of host-
gene, injection of DC-HIL-expressing myeloid-derived suppressor cells (MDSC), or induction of sDC-HIL expression.
Nonresponders expressed significantly higher levels of baseline sDC-HIL levels than responders. Among patients (
= 28) for fluctuation with time, nonresponders (14/15 cases) showed increasing or persistently elevated levels. Responders (12/13) had decreasing or persistently low levels. Among various tumors, B16 melanoma exhibited resistance to anti-PDL1 but responded to anti-DC-HIL mAb. Using B16 melanoma and LL2 lung cancer, we showed that deletion of host-derived DC-HIL expression converted the resistant tumor to one responsive to anti-PDL1 mAb. The responsive state was reversed by infusion of DC-HIL
MDSC or induction of sDC-HIL expression.
sDC-HIL in the blood and probably DC-HIL receptor expressed by MDSC play an important role in regulating response to ICI in advanced NSCLC.</description><identifier>ISSN: 1078-0432</identifier><identifier>EISSN: 1557-3265</identifier><identifier>DOI: 10.1158/1078-0432.CCR-19-2360</identifier><identifier>PMID: 31822499</identifier><language>eng</language><publisher>United States</publisher><subject>Adult ; Aged ; Aged, 80 and over ; Animals ; Antibodies, Monoclonal - pharmacology ; B7-H1 Antigen - antagonists & inhibitors ; B7-H1 Antigen - immunology ; B7-H1 Antigen - metabolism ; Carcinoma, Non-Small-Cell Lung - immunology ; Carcinoma, Non-Small-Cell Lung - metabolism ; Carcinoma, Non-Small-Cell Lung - pathology ; Carcinoma, Non-Small-Cell Lung - therapy ; Cell Line, Tumor ; Disease Models, Animal ; Female ; Humans ; Immunologic Factors - metabolism ; Immunotherapy - methods ; Lung Neoplasms - immunology ; Lung Neoplasms - metabolism ; Lung Neoplasms - secondary ; Lung Neoplasms - therapy ; Male ; Melanoma, Experimental - immunology ; Melanoma, Experimental - metabolism ; Melanoma, Experimental - pathology ; Melanoma, Experimental - therapy ; Membrane Glycoproteins - immunology ; Membrane Glycoproteins - metabolism ; Mice ; Mice, Inbred C57BL ; Middle Aged ; Myeloid-Derived Suppressor Cells - immunology ; Skin Neoplasms - immunology ; Skin Neoplasms - metabolism ; Skin Neoplasms - pathology ; Skin Neoplasms - therapy</subject><ispartof>Clinical cancer research, 2020-03, Vol.26 (6), p.1449-1459</ispartof><rights>2019 American Association for Cancer Research.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c422t-be040feecc0838495acc7d1fa44253851516c6684922bb16bd23c532c517810c3</citedby><cites>FETCH-LOGICAL-c422t-be040feecc0838495acc7d1fa44253851516c6684922bb16bd23c532c517810c3</cites><orcidid>0000-0002-6630-4440 ; 0000-0003-2837-842X ; 0000-0002-7812-6741</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780,3343,27901,27902</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/31822499$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Chung, Jin-Sung</creatorcontrib><creatorcontrib>Ramani, Vijay</creatorcontrib><creatorcontrib>Kobayashi, Masato</creatorcontrib><creatorcontrib>Fattah, Farjana</creatorcontrib><creatorcontrib>Popat, Vinita</creatorcontrib><creatorcontrib>Zhang, Song</creatorcontrib><creatorcontrib>Cruz, Jr, Ponciano D</creatorcontrib><creatorcontrib>Gerber, David E</creatorcontrib><creatorcontrib>Ariizumi, Kiyoshi</creatorcontrib><title>DC-HIL/Gpnmb Is a Negative Regulator of Tumor Response to Immune Checkpoint Inhibitors</title><title>Clinical cancer research</title><addtitle>Clin Cancer Res</addtitle><description>Immune checkpoint inhibitors (ICI) benefit only a minority of treated patients with cancer. Identification of biomarkers distinguishing responders and nonresponders will improve management of patients with cancer. Because the DC-HIL checkpoint differs from the PD1 pathway in expression and inhibitory mechanisms, we examined whether DC-HIL expression regulates ICI responsiveness.
Plasma samples were collected from patients with advanced non-small cell lung carcinoma (NSCLC) (
= 76) at baseline and/or follow-up after ICI monotherapy. Blood-soluble DC-HIL (sDC-HIL) was determined and analyzed for correlation with the early tumor response. To study the mechanisms, we measured effect of anti-DC-HIL versus anti-PDL1 mAb on growth of mouse tumor cells in experimentally metastatic lung. Influence of DC-HIL to anti-PDL1 treatment was assessed by changes in tumor response after deletion of host-
gene, injection of DC-HIL-expressing myeloid-derived suppressor cells (MDSC), or induction of sDC-HIL expression.
Nonresponders expressed significantly higher levels of baseline sDC-HIL levels than responders. Among patients (
= 28) for fluctuation with time, nonresponders (14/15 cases) showed increasing or persistently elevated levels. Responders (12/13) had decreasing or persistently low levels. Among various tumors, B16 melanoma exhibited resistance to anti-PDL1 but responded to anti-DC-HIL mAb. Using B16 melanoma and LL2 lung cancer, we showed that deletion of host-derived DC-HIL expression converted the resistant tumor to one responsive to anti-PDL1 mAb. The responsive state was reversed by infusion of DC-HIL
MDSC or induction of sDC-HIL expression.
sDC-HIL in the blood and probably DC-HIL receptor expressed by MDSC play an important role in regulating response to ICI in advanced NSCLC.</description><subject>Adult</subject><subject>Aged</subject><subject>Aged, 80 and over</subject><subject>Animals</subject><subject>Antibodies, Monoclonal - pharmacology</subject><subject>B7-H1 Antigen - antagonists & inhibitors</subject><subject>B7-H1 Antigen - immunology</subject><subject>B7-H1 Antigen - metabolism</subject><subject>Carcinoma, Non-Small-Cell Lung - immunology</subject><subject>Carcinoma, Non-Small-Cell Lung - metabolism</subject><subject>Carcinoma, Non-Small-Cell Lung - pathology</subject><subject>Carcinoma, Non-Small-Cell Lung - therapy</subject><subject>Cell Line, Tumor</subject><subject>Disease Models, Animal</subject><subject>Female</subject><subject>Humans</subject><subject>Immunologic Factors - metabolism</subject><subject>Immunotherapy - methods</subject><subject>Lung Neoplasms - immunology</subject><subject>Lung Neoplasms - metabolism</subject><subject>Lung Neoplasms - secondary</subject><subject>Lung Neoplasms - therapy</subject><subject>Male</subject><subject>Melanoma, Experimental - immunology</subject><subject>Melanoma, Experimental - metabolism</subject><subject>Melanoma, Experimental - pathology</subject><subject>Melanoma, Experimental - therapy</subject><subject>Membrane Glycoproteins - immunology</subject><subject>Membrane Glycoproteins - metabolism</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Middle Aged</subject><subject>Myeloid-Derived Suppressor Cells - immunology</subject><subject>Skin Neoplasms - immunology</subject><subject>Skin Neoplasms - metabolism</subject><subject>Skin Neoplasms - pathology</subject><subject>Skin Neoplasms - therapy</subject><issn>1078-0432</issn><issn>1557-3265</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2020</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNo9kF1LwzAUhoMoTqc_QcmlN9ly8tGPS6m6FYbCmN6GNEu3atvUphX897Zs8-q8cN7nHHgQugM6A5DRHGgYESo4myXJmkBMGA_oGboCKUPCWSDPh3zqTNC195-UggAqLtGEQ8SYiOMr9PGUkGW6mi-auspw6rHGr3anu-LH4rXd9aXuXItdjjd9NYS19Y2rvcWdw2lV9bXFyd6ar8YVdYfTel9kxQD4G3SR69Lb2-OcoveX502yJKu3RZo8rogRjHUks1TQ3FpjaMQjEUttTLiFXAvBJI8kSAhMEAwbxrIMgmzLuJGcGQlhBNTwKXo43G1a991b36mq8MaWpa6t671inI1sJIKhKg9V0zrvW5urpi0q3f4qoGpUqkZdatSlBqUKYjUqHbj744s-q-z2nzo55H8c-HAp</recordid><startdate>20200315</startdate><enddate>20200315</enddate><creator>Chung, Jin-Sung</creator><creator>Ramani, Vijay</creator><creator>Kobayashi, Masato</creator><creator>Fattah, Farjana</creator><creator>Popat, Vinita</creator><creator>Zhang, Song</creator><creator>Cruz, Jr, Ponciano D</creator><creator>Gerber, David E</creator><creator>Ariizumi, Kiyoshi</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><orcidid>https://orcid.org/0000-0002-6630-4440</orcidid><orcidid>https://orcid.org/0000-0003-2837-842X</orcidid><orcidid>https://orcid.org/0000-0002-7812-6741</orcidid></search><sort><creationdate>20200315</creationdate><title>DC-HIL/Gpnmb Is a Negative Regulator of Tumor Response to Immune Checkpoint Inhibitors</title><author>Chung, Jin-Sung ; 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Identification of biomarkers distinguishing responders and nonresponders will improve management of patients with cancer. Because the DC-HIL checkpoint differs from the PD1 pathway in expression and inhibitory mechanisms, we examined whether DC-HIL expression regulates ICI responsiveness.
Plasma samples were collected from patients with advanced non-small cell lung carcinoma (NSCLC) (
= 76) at baseline and/or follow-up after ICI monotherapy. Blood-soluble DC-HIL (sDC-HIL) was determined and analyzed for correlation with the early tumor response. To study the mechanisms, we measured effect of anti-DC-HIL versus anti-PDL1 mAb on growth of mouse tumor cells in experimentally metastatic lung. Influence of DC-HIL to anti-PDL1 treatment was assessed by changes in tumor response after deletion of host-
gene, injection of DC-HIL-expressing myeloid-derived suppressor cells (MDSC), or induction of sDC-HIL expression.
Nonresponders expressed significantly higher levels of baseline sDC-HIL levels than responders. Among patients (
= 28) for fluctuation with time, nonresponders (14/15 cases) showed increasing or persistently elevated levels. Responders (12/13) had decreasing or persistently low levels. Among various tumors, B16 melanoma exhibited resistance to anti-PDL1 but responded to anti-DC-HIL mAb. Using B16 melanoma and LL2 lung cancer, we showed that deletion of host-derived DC-HIL expression converted the resistant tumor to one responsive to anti-PDL1 mAb. The responsive state was reversed by infusion of DC-HIL
MDSC or induction of sDC-HIL expression.
sDC-HIL in the blood and probably DC-HIL receptor expressed by MDSC play an important role in regulating response to ICI in advanced NSCLC.</abstract><cop>United States</cop><pmid>31822499</pmid><doi>10.1158/1078-0432.CCR-19-2360</doi><tpages>11</tpages><orcidid>https://orcid.org/0000-0002-6630-4440</orcidid><orcidid>https://orcid.org/0000-0003-2837-842X</orcidid><orcidid>https://orcid.org/0000-0002-7812-6741</orcidid><oa>free_for_read</oa></addata></record> |
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| subjects | Adult Aged Aged, 80 and over Animals Antibodies, Monoclonal - pharmacology B7-H1 Antigen - antagonists & inhibitors B7-H1 Antigen - immunology B7-H1 Antigen - metabolism Carcinoma, Non-Small-Cell Lung - immunology Carcinoma, Non-Small-Cell Lung - metabolism Carcinoma, Non-Small-Cell Lung - pathology Carcinoma, Non-Small-Cell Lung - therapy Cell Line, Tumor Disease Models, Animal Female Humans Immunologic Factors - metabolism Immunotherapy - methods Lung Neoplasms - immunology Lung Neoplasms - metabolism Lung Neoplasms - secondary Lung Neoplasms - therapy Male Melanoma, Experimental - immunology Melanoma, Experimental - metabolism Melanoma, Experimental - pathology Melanoma, Experimental - therapy Membrane Glycoproteins - immunology Membrane Glycoproteins - metabolism Mice Mice, Inbred C57BL Middle Aged Myeloid-Derived Suppressor Cells - immunology Skin Neoplasms - immunology Skin Neoplasms - metabolism Skin Neoplasms - pathology Skin Neoplasms - therapy |
| title | DC-HIL/Gpnmb Is a Negative Regulator of Tumor Response to Immune Checkpoint Inhibitors |
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