Evolution of delayed resistance to immunotherapy in a melanoma responder

Despite initial responses 1 – 3 , most melanoma patients develop resistance 4 to immune checkpoint blockade (ICB). To understand the evolution of resistance, we studied 37 tumor samples over 9 years from a patient with metastatic melanoma with complete clinical response to ICB followed by delayed re...

Ausführliche Beschreibung

Gespeichert in:
Bibliographische Detailangaben
Veröffentlicht in:Nature medicine 2021-06, Vol.27 (6), p.985-992
Hauptverfasser: Liu, David, Lin, Jia-Ren, Robitschek, Emily J., Kasumova, Gyulnara G., Heyde, Alex, Shi, Alvin, Kraya, Adam, Zhang, Gao, Moll, Tabea, Frederick, Dennie T., Chen, Yu-An, Wang, Shu, Schapiro, Denis, Ho, Li-Lun, Bi, Kevin, Sahu, Avinash, Mei, Shaolin, Miao, Benchun, Sharova, Tatyana, Alvarez-Breckenridge, Christopher, Stocking, Jackson H., Kim, Tommy, Fadden, Riley, Lawrence, Donald, Hoang, Mai P., Cahill, Daniel P., Malehmir, Mohsen, Nowak, Martin A., Brastianos, Priscilla K., Lian, Christine G., Ruppin, Eytan, Izar, Benjamin, Herlyn, Meenhard, Van Allen, Eliezer M., Nathanson, Katherine, Flaherty, Keith T., Sullivan, Ryan J., Kellis, Manolis, Sorger, Peter K., Boland, Genevieve M.
Format: Artikel
Sprache:eng
Schlagworte:
Online-Zugang:Volltext
Tags: Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
container_end_page 992
container_issue 6
container_start_page 985
container_title Nature medicine
container_volume 27
creator Liu, David
Lin, Jia-Ren
Robitschek, Emily J.
Kasumova, Gyulnara G.
Heyde, Alex
Shi, Alvin
Kraya, Adam
Zhang, Gao
Moll, Tabea
Frederick, Dennie T.
Chen, Yu-An
Wang, Shu
Schapiro, Denis
Ho, Li-Lun
Bi, Kevin
Sahu, Avinash
Mei, Shaolin
Miao, Benchun
Sharova, Tatyana
Alvarez-Breckenridge, Christopher
Stocking, Jackson H.
Kim, Tommy
Fadden, Riley
Lawrence, Donald
Hoang, Mai P.
Cahill, Daniel P.
Malehmir, Mohsen
Nowak, Martin A.
Brastianos, Priscilla K.
Lian, Christine G.
Ruppin, Eytan
Izar, Benjamin
Herlyn, Meenhard
Van Allen, Eliezer M.
Nathanson, Katherine
Flaherty, Keith T.
Sullivan, Ryan J.
Kellis, Manolis
Sorger, Peter K.
Boland, Genevieve M.
description Despite initial responses 1 – 3 , most melanoma patients develop resistance 4 to immune checkpoint blockade (ICB). To understand the evolution of resistance, we studied 37 tumor samples over 9 years from a patient with metastatic melanoma with complete clinical response to ICB followed by delayed recurrence and death. Phylogenetic analysis revealed co-evolution of seven lineages with multiple convergent, but independent resistance-associated alterations. All recurrent tumors emerged from a lineage characterized by loss of chromosome 15q, with post-treatment clones acquiring additional genomic driver events. Deconvolution of bulk RNA sequencing and highly multiplexed immunofluorescence (t-CyCIF) revealed differences in immune composition among different lineages. Imaging revealed a vasculogenic mimicry phenotype in NGFR hi tumor cells with high PD-L1 expression in close proximity to immune cells. Rapid autopsy demonstrated two distinct NGFR spatial patterns with high polarity and proximity to immune cells in subcutaneous tumors versus a diffuse spatial pattern in lung tumors, suggesting different roles of this neural-crest-like program in different tumor microenvironments. Broadly, this study establishes a high-resolution map of the evolutionary dynamics of resistance to ICB, characterizes a de-differentiated neural-crest tumor population in melanoma immunotherapy resistance and describes site-specific differences in tumor–immune interactions via longitudinal analysis of a patient with melanoma with an unusual clinical course. Genetic and protein expression analyses of serially collected tumor biopsies from a patient with melanoma treated with immune checkpoint inhibitors provide insights into tumor microenvironment changes that occur during treatment resistance.
doi_str_mv 10.1038/s41591-021-01331-8
format Article
fullrecord <record><control><sourceid>proquest_pubme</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_8474080</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>2522191767</sourcerecordid><originalsourceid>FETCH-LOGICAL-c540t-f2232a1efe18ad591f55dcff6688fefc6fb02f57ecfb7b7e0baf423e561ddb363</originalsourceid><addsrcrecordid>eNqNkU1rFTEUhoMotl79Ay5kwI1QRvMxyWQ2glxaKxTcKLgLmcxJmzKTXJOZyv33nuvU68dCXIQE8ryH8_IQ8pzR14wK_aY0THasphwPE4LV-gE5ZbJRNWvpl4f4pq2udSfVCXlSyi2lVFDZPSYnQnQN6zg_JZfnd2lc5pBilXw1wGj3MFQZSiizjQ6qOVVhmpaY5hvIdrevQqxsNSEY02QP5C7FAfJT8sjbscCz-3tDPl-cf9pe1lcf33_YvruqnWzoXHvOBbcMPDBtB1zfSzk475XS2oN3yveUe9mC833bt0B76xsuQCo2DL1QYkPernN3Sz_B4CDO2Y5ml8Nk894kG8yfPzHcmOt0Z3TTNlRTHPDqfkBOXxcos5lCcTBiIUhLMVxyzjrWqhbRl3-ht2nJEesh1TCGVVqBFF8pl1MpGfxxGUbNQZRZRRkUZX6IMhpDL36vcYz8NIPA2Qp8gz754gKgjSOGKlWjJFMcXzhzQ_T_09sw24PxbVrijFGxRgvi8Rryr5L_2P87UTzBLQ</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>2541123273</pqid></control><display><type>article</type><title>Evolution of delayed resistance to immunotherapy in a melanoma responder</title><source>MEDLINE</source><source>Nature</source><source>Web of Science - Science Citation Index Expanded - 2021&lt;img src="https://exlibris-pub.s3.amazonaws.com/fromwos-v2.jpg" /&gt;</source><source>Alma/SFX Local Collection</source><creator>Liu, David ; Lin, Jia-Ren ; Robitschek, Emily J. ; Kasumova, Gyulnara G. ; Heyde, Alex ; Shi, Alvin ; Kraya, Adam ; Zhang, Gao ; Moll, Tabea ; Frederick, Dennie T. ; Chen, Yu-An ; Wang, Shu ; Schapiro, Denis ; Ho, Li-Lun ; Bi, Kevin ; Sahu, Avinash ; Mei, Shaolin ; Miao, Benchun ; Sharova, Tatyana ; Alvarez-Breckenridge, Christopher ; Stocking, Jackson H. ; Kim, Tommy ; Fadden, Riley ; Lawrence, Donald ; Hoang, Mai P. ; Cahill, Daniel P. ; Malehmir, Mohsen ; Nowak, Martin A. ; Brastianos, Priscilla K. ; Lian, Christine G. ; Ruppin, Eytan ; Izar, Benjamin ; Herlyn, Meenhard ; Van Allen, Eliezer M. ; Nathanson, Katherine ; Flaherty, Keith T. ; Sullivan, Ryan J. ; Kellis, Manolis ; Sorger, Peter K. ; Boland, Genevieve M.</creator><creatorcontrib>Liu, David ; Lin, Jia-Ren ; Robitschek, Emily J. ; Kasumova, Gyulnara G. ; Heyde, Alex ; Shi, Alvin ; Kraya, Adam ; Zhang, Gao ; Moll, Tabea ; Frederick, Dennie T. ; Chen, Yu-An ; Wang, Shu ; Schapiro, Denis ; Ho, Li-Lun ; Bi, Kevin ; Sahu, Avinash ; Mei, Shaolin ; Miao, Benchun ; Sharova, Tatyana ; Alvarez-Breckenridge, Christopher ; Stocking, Jackson H. ; Kim, Tommy ; Fadden, Riley ; Lawrence, Donald ; Hoang, Mai P. ; Cahill, Daniel P. ; Malehmir, Mohsen ; Nowak, Martin A. ; Brastianos, Priscilla K. ; Lian, Christine G. ; Ruppin, Eytan ; Izar, Benjamin ; Herlyn, Meenhard ; Van Allen, Eliezer M. ; Nathanson, Katherine ; Flaherty, Keith T. ; Sullivan, Ryan J. ; Kellis, Manolis ; Sorger, Peter K. ; Boland, Genevieve M.</creatorcontrib><description>Despite initial responses 1 – 3 , most melanoma patients develop resistance 4 to immune checkpoint blockade (ICB). To understand the evolution of resistance, we studied 37 tumor samples over 9 years from a patient with metastatic melanoma with complete clinical response to ICB followed by delayed recurrence and death. Phylogenetic analysis revealed co-evolution of seven lineages with multiple convergent, but independent resistance-associated alterations. All recurrent tumors emerged from a lineage characterized by loss of chromosome 15q, with post-treatment clones acquiring additional genomic driver events. Deconvolution of bulk RNA sequencing and highly multiplexed immunofluorescence (t-CyCIF) revealed differences in immune composition among different lineages. Imaging revealed a vasculogenic mimicry phenotype in NGFR hi tumor cells with high PD-L1 expression in close proximity to immune cells. Rapid autopsy demonstrated two distinct NGFR spatial patterns with high polarity and proximity to immune cells in subcutaneous tumors versus a diffuse spatial pattern in lung tumors, suggesting different roles of this neural-crest-like program in different tumor microenvironments. Broadly, this study establishes a high-resolution map of the evolutionary dynamics of resistance to ICB, characterizes a de-differentiated neural-crest tumor population in melanoma immunotherapy resistance and describes site-specific differences in tumor–immune interactions via longitudinal analysis of a patient with melanoma with an unusual clinical course. Genetic and protein expression analyses of serially collected tumor biopsies from a patient with melanoma treated with immune checkpoint inhibitors provide insights into tumor microenvironment changes that occur during treatment resistance.</description><identifier>ISSN: 1078-8956</identifier><identifier>ISSN: 1546-170X</identifier><identifier>EISSN: 1546-170X</identifier><identifier>DOI: 10.1038/s41591-021-01331-8</identifier><identifier>PMID: 33941922</identifier><language>eng</language><publisher>New York: Nature Publishing Group US</publisher><subject><![CDATA[631/67/1059/2325 ; 631/67/1059/2326 ; 631/67/1813/1634 ; 631/67/69 ; Autopsies ; Autopsy ; B7-H1 Antigen - antagonists & inhibitors ; B7-H1 Antigen - genetics ; B7-H1 Antigen - immunology ; Biochemistry & Molecular Biology ; Biomedical and Life Sciences ; Biomedicine ; Cancer Research ; Cell Biology ; Chromosome 15 ; Chromosomes, Human, Pair 15 - genetics ; Coevolution ; Drug Resistance, Neoplasm - drug effects ; Evolution ; Female ; Gene Expression Regulation, Neoplastic ; Gene sequencing ; Genetic analysis ; Humans ; Immune checkpoint inhibitors ; Immune Checkpoint Inhibitors - adverse effects ; Immune Checkpoint Inhibitors - therapeutic use ; Immune system ; Immunofluorescence ; Immunotherapy ; Immunotherapy - adverse effects ; Infectious Diseases ; Letter ; Life Sciences & Biomedicine ; Male ; Medicine, Research & Experimental ; Melanoma ; Melanoma - genetics ; Melanoma - immunology ; Melanoma - pathology ; Melanoma - therapy ; Metabolic Diseases ; Metastases ; Microenvironments ; Mimicry ; Molecular Medicine ; Neoplasm Metastasis ; Neoplasm Recurrence, Local - genetics ; Neoplasm Recurrence, Local - immunology ; Neoplasm Recurrence, Local - pathology ; Neoplasm Recurrence, Local - therapy ; Nerve growth factor receptors ; Nerve Tissue Proteins - genetics ; Nerve Tissue Proteins - immunology ; Neurosciences ; Patients ; PD-L1 protein ; Phenotypes ; Phylogeny ; Polarity ; Receptors, Nerve Growth Factor - genetics ; Receptors, Nerve Growth Factor - immunology ; Research & Experimental Medicine ; Science & Technology ; Tumor cells ; Tumor microenvironment ; Tumor Microenvironment - drug effects ; Tumors]]></subject><ispartof>Nature medicine, 2021-06, Vol.27 (6), p.985-992</ispartof><rights>The Author(s), under exclusive licence to Springer Nature America, Inc. 2021</rights><rights>The Author(s), under exclusive licence to Springer Nature America, Inc. 2021.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>true</woscitedreferencessubscribed><woscitedreferencescount>63</woscitedreferencescount><woscitedreferencesoriginalsourcerecordid>wos000646516200001</woscitedreferencesoriginalsourcerecordid><citedby>FETCH-LOGICAL-c540t-f2232a1efe18ad591f55dcff6688fefc6fb02f57ecfb7b7e0baf423e561ddb363</citedby><cites>FETCH-LOGICAL-c540t-f2232a1efe18ad591f55dcff6688fefc6fb02f57ecfb7b7e0baf423e561ddb363</cites><orcidid>0000-0001-5344-6645 ; 0000-0002-7862-3940 ; 0000-0002-7522-6173 ; 0000-0001-7228-4696 ; 0000-0003-2759-2125 ; 0000-0002-6740-0901 ; 0000-0001-5489-0908 ; 0000-0002-0201-4444 ; 0000-0002-9391-5722 ; 0000-0002-1406-7981 ; 0000-0001-6915-5850 ; 0000-0003-2379-6702 ; 0000-0002-3364-1838 ; 0000-0003-0839-0739 ; 0000-0001-7113-9630 ; 0000-0003-4702-7705 ; 0000-0003-4470-8425 ; 0000-0002-2771-0155 ; 0000-0003-0346-5033 ; 0000-0002-1178-1143 ; 0000-0002-2193-764X</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,315,782,786,887,27931,27932,39265</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/33941922$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Liu, David</creatorcontrib><creatorcontrib>Lin, Jia-Ren</creatorcontrib><creatorcontrib>Robitschek, Emily J.</creatorcontrib><creatorcontrib>Kasumova, Gyulnara G.</creatorcontrib><creatorcontrib>Heyde, Alex</creatorcontrib><creatorcontrib>Shi, Alvin</creatorcontrib><creatorcontrib>Kraya, Adam</creatorcontrib><creatorcontrib>Zhang, Gao</creatorcontrib><creatorcontrib>Moll, Tabea</creatorcontrib><creatorcontrib>Frederick, Dennie T.</creatorcontrib><creatorcontrib>Chen, Yu-An</creatorcontrib><creatorcontrib>Wang, Shu</creatorcontrib><creatorcontrib>Schapiro, Denis</creatorcontrib><creatorcontrib>Ho, Li-Lun</creatorcontrib><creatorcontrib>Bi, Kevin</creatorcontrib><creatorcontrib>Sahu, Avinash</creatorcontrib><creatorcontrib>Mei, Shaolin</creatorcontrib><creatorcontrib>Miao, Benchun</creatorcontrib><creatorcontrib>Sharova, Tatyana</creatorcontrib><creatorcontrib>Alvarez-Breckenridge, Christopher</creatorcontrib><creatorcontrib>Stocking, Jackson H.</creatorcontrib><creatorcontrib>Kim, Tommy</creatorcontrib><creatorcontrib>Fadden, Riley</creatorcontrib><creatorcontrib>Lawrence, Donald</creatorcontrib><creatorcontrib>Hoang, Mai P.</creatorcontrib><creatorcontrib>Cahill, Daniel P.</creatorcontrib><creatorcontrib>Malehmir, Mohsen</creatorcontrib><creatorcontrib>Nowak, Martin A.</creatorcontrib><creatorcontrib>Brastianos, Priscilla K.</creatorcontrib><creatorcontrib>Lian, Christine G.</creatorcontrib><creatorcontrib>Ruppin, Eytan</creatorcontrib><creatorcontrib>Izar, Benjamin</creatorcontrib><creatorcontrib>Herlyn, Meenhard</creatorcontrib><creatorcontrib>Van Allen, Eliezer M.</creatorcontrib><creatorcontrib>Nathanson, Katherine</creatorcontrib><creatorcontrib>Flaherty, Keith T.</creatorcontrib><creatorcontrib>Sullivan, Ryan J.</creatorcontrib><creatorcontrib>Kellis, Manolis</creatorcontrib><creatorcontrib>Sorger, Peter K.</creatorcontrib><creatorcontrib>Boland, Genevieve M.</creatorcontrib><title>Evolution of delayed resistance to immunotherapy in a melanoma responder</title><title>Nature medicine</title><addtitle>Nat Med</addtitle><addtitle>NAT MED</addtitle><addtitle>Nat Med</addtitle><description>Despite initial responses 1 – 3 , most melanoma patients develop resistance 4 to immune checkpoint blockade (ICB). To understand the evolution of resistance, we studied 37 tumor samples over 9 years from a patient with metastatic melanoma with complete clinical response to ICB followed by delayed recurrence and death. Phylogenetic analysis revealed co-evolution of seven lineages with multiple convergent, but independent resistance-associated alterations. All recurrent tumors emerged from a lineage characterized by loss of chromosome 15q, with post-treatment clones acquiring additional genomic driver events. Deconvolution of bulk RNA sequencing and highly multiplexed immunofluorescence (t-CyCIF) revealed differences in immune composition among different lineages. Imaging revealed a vasculogenic mimicry phenotype in NGFR hi tumor cells with high PD-L1 expression in close proximity to immune cells. Rapid autopsy demonstrated two distinct NGFR spatial patterns with high polarity and proximity to immune cells in subcutaneous tumors versus a diffuse spatial pattern in lung tumors, suggesting different roles of this neural-crest-like program in different tumor microenvironments. Broadly, this study establishes a high-resolution map of the evolutionary dynamics of resistance to ICB, characterizes a de-differentiated neural-crest tumor population in melanoma immunotherapy resistance and describes site-specific differences in tumor–immune interactions via longitudinal analysis of a patient with melanoma with an unusual clinical course. Genetic and protein expression analyses of serially collected tumor biopsies from a patient with melanoma treated with immune checkpoint inhibitors provide insights into tumor microenvironment changes that occur during treatment resistance.</description><subject>631/67/1059/2325</subject><subject>631/67/1059/2326</subject><subject>631/67/1813/1634</subject><subject>631/67/69</subject><subject>Autopsies</subject><subject>Autopsy</subject><subject>B7-H1 Antigen - antagonists &amp; inhibitors</subject><subject>B7-H1 Antigen - genetics</subject><subject>B7-H1 Antigen - immunology</subject><subject>Biochemistry &amp; Molecular Biology</subject><subject>Biomedical and Life Sciences</subject><subject>Biomedicine</subject><subject>Cancer Research</subject><subject>Cell Biology</subject><subject>Chromosome 15</subject><subject>Chromosomes, Human, Pair 15 - genetics</subject><subject>Coevolution</subject><subject>Drug Resistance, Neoplasm - drug effects</subject><subject>Evolution</subject><subject>Female</subject><subject>Gene Expression Regulation, Neoplastic</subject><subject>Gene sequencing</subject><subject>Genetic analysis</subject><subject>Humans</subject><subject>Immune checkpoint inhibitors</subject><subject>Immune Checkpoint Inhibitors - adverse effects</subject><subject>Immune Checkpoint Inhibitors - therapeutic use</subject><subject>Immune system</subject><subject>Immunofluorescence</subject><subject>Immunotherapy</subject><subject>Immunotherapy - adverse effects</subject><subject>Infectious Diseases</subject><subject>Letter</subject><subject>Life Sciences &amp; Biomedicine</subject><subject>Male</subject><subject>Medicine, Research &amp; Experimental</subject><subject>Melanoma</subject><subject>Melanoma - genetics</subject><subject>Melanoma - immunology</subject><subject>Melanoma - pathology</subject><subject>Melanoma - therapy</subject><subject>Metabolic Diseases</subject><subject>Metastases</subject><subject>Microenvironments</subject><subject>Mimicry</subject><subject>Molecular Medicine</subject><subject>Neoplasm Metastasis</subject><subject>Neoplasm Recurrence, Local - genetics</subject><subject>Neoplasm Recurrence, Local - immunology</subject><subject>Neoplasm Recurrence, Local - pathology</subject><subject>Neoplasm Recurrence, Local - therapy</subject><subject>Nerve growth factor receptors</subject><subject>Nerve Tissue Proteins - genetics</subject><subject>Nerve Tissue Proteins - immunology</subject><subject>Neurosciences</subject><subject>Patients</subject><subject>PD-L1 protein</subject><subject>Phenotypes</subject><subject>Phylogeny</subject><subject>Polarity</subject><subject>Receptors, Nerve Growth Factor - genetics</subject><subject>Receptors, Nerve Growth Factor - immunology</subject><subject>Research &amp; Experimental Medicine</subject><subject>Science &amp; Technology</subject><subject>Tumor cells</subject><subject>Tumor microenvironment</subject><subject>Tumor Microenvironment - drug effects</subject><subject>Tumors</subject><issn>1078-8956</issn><issn>1546-170X</issn><issn>1546-170X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2021</creationdate><recordtype>article</recordtype><sourceid>HGBXW</sourceid><sourceid>EIF</sourceid><sourceid>8G5</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><sourceid>GUQSH</sourceid><sourceid>M2O</sourceid><recordid>eNqNkU1rFTEUhoMotl79Ay5kwI1QRvMxyWQ2glxaKxTcKLgLmcxJmzKTXJOZyv33nuvU68dCXIQE8ryH8_IQ8pzR14wK_aY0THasphwPE4LV-gE5ZbJRNWvpl4f4pq2udSfVCXlSyi2lVFDZPSYnQnQN6zg_JZfnd2lc5pBilXw1wGj3MFQZSiizjQ6qOVVhmpaY5hvIdrevQqxsNSEY02QP5C7FAfJT8sjbscCz-3tDPl-cf9pe1lcf33_YvruqnWzoXHvOBbcMPDBtB1zfSzk475XS2oN3yveUe9mC833bt0B76xsuQCo2DL1QYkPernN3Sz_B4CDO2Y5ml8Nk894kG8yfPzHcmOt0Z3TTNlRTHPDqfkBOXxcos5lCcTBiIUhLMVxyzjrWqhbRl3-ht2nJEesh1TCGVVqBFF8pl1MpGfxxGUbNQZRZRRkUZX6IMhpDL36vcYz8NIPA2Qp8gz754gKgjSOGKlWjJFMcXzhzQ_T_09sw24PxbVrijFGxRgvi8Rryr5L_2P87UTzBLQ</recordid><startdate>20210601</startdate><enddate>20210601</enddate><creator>Liu, David</creator><creator>Lin, Jia-Ren</creator><creator>Robitschek, Emily J.</creator><creator>Kasumova, Gyulnara G.</creator><creator>Heyde, Alex</creator><creator>Shi, Alvin</creator><creator>Kraya, Adam</creator><creator>Zhang, Gao</creator><creator>Moll, Tabea</creator><creator>Frederick, Dennie T.</creator><creator>Chen, Yu-An</creator><creator>Wang, Shu</creator><creator>Schapiro, Denis</creator><creator>Ho, Li-Lun</creator><creator>Bi, Kevin</creator><creator>Sahu, Avinash</creator><creator>Mei, Shaolin</creator><creator>Miao, Benchun</creator><creator>Sharova, Tatyana</creator><creator>Alvarez-Breckenridge, Christopher</creator><creator>Stocking, Jackson H.</creator><creator>Kim, Tommy</creator><creator>Fadden, Riley</creator><creator>Lawrence, Donald</creator><creator>Hoang, Mai P.</creator><creator>Cahill, Daniel P.</creator><creator>Malehmir, Mohsen</creator><creator>Nowak, Martin A.</creator><creator>Brastianos, Priscilla K.</creator><creator>Lian, Christine G.</creator><creator>Ruppin, Eytan</creator><creator>Izar, Benjamin</creator><creator>Herlyn, Meenhard</creator><creator>Van Allen, Eliezer M.</creator><creator>Nathanson, Katherine</creator><creator>Flaherty, Keith T.</creator><creator>Sullivan, Ryan J.</creator><creator>Kellis, Manolis</creator><creator>Sorger, Peter K.</creator><creator>Boland, Genevieve M.</creator><general>Nature Publishing Group US</general><general>NATURE PORTFOLIO</general><general>Nature Publishing Group</general><scope>BLEPL</scope><scope>DTL</scope><scope>HGBXW</scope><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>3V.</scope><scope>7QG</scope><scope>7QL</scope><scope>7QP</scope><scope>7QR</scope><scope>7T5</scope><scope>7TK</scope><scope>7TM</scope><scope>7TO</scope><scope>7U7</scope><scope>7U9</scope><scope>7X7</scope><scope>7XB</scope><scope>88A</scope><scope>88E</scope><scope>88I</scope><scope>8AO</scope><scope>8FD</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>8G5</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>C1K</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>GUQSH</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>LK8</scope><scope>M0S</scope><scope>M1P</scope><scope>M2O</scope><scope>M2P</scope><scope>M7N</scope><scope>M7P</scope><scope>MBDVC</scope><scope>P64</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>Q9U</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0001-5344-6645</orcidid><orcidid>https://orcid.org/0000-0002-7862-3940</orcidid><orcidid>https://orcid.org/0000-0002-7522-6173</orcidid><orcidid>https://orcid.org/0000-0001-7228-4696</orcidid><orcidid>https://orcid.org/0000-0003-2759-2125</orcidid><orcidid>https://orcid.org/0000-0002-6740-0901</orcidid><orcidid>https://orcid.org/0000-0001-5489-0908</orcidid><orcidid>https://orcid.org/0000-0002-0201-4444</orcidid><orcidid>https://orcid.org/0000-0002-9391-5722</orcidid><orcidid>https://orcid.org/0000-0002-1406-7981</orcidid><orcidid>https://orcid.org/0000-0001-6915-5850</orcidid><orcidid>https://orcid.org/0000-0003-2379-6702</orcidid><orcidid>https://orcid.org/0000-0002-3364-1838</orcidid><orcidid>https://orcid.org/0000-0003-0839-0739</orcidid><orcidid>https://orcid.org/0000-0001-7113-9630</orcidid><orcidid>https://orcid.org/0000-0003-4702-7705</orcidid><orcidid>https://orcid.org/0000-0003-4470-8425</orcidid><orcidid>https://orcid.org/0000-0002-2771-0155</orcidid><orcidid>https://orcid.org/0000-0003-0346-5033</orcidid><orcidid>https://orcid.org/0000-0002-1178-1143</orcidid><orcidid>https://orcid.org/0000-0002-2193-764X</orcidid></search><sort><creationdate>20210601</creationdate><title>Evolution of delayed resistance to immunotherapy in a melanoma responder</title><author>Liu, David ; Lin, Jia-Ren ; Robitschek, Emily J. ; Kasumova, Gyulnara G. ; Heyde, Alex ; Shi, Alvin ; Kraya, Adam ; Zhang, Gao ; Moll, Tabea ; Frederick, Dennie T. ; Chen, Yu-An ; Wang, Shu ; Schapiro, Denis ; Ho, Li-Lun ; Bi, Kevin ; Sahu, Avinash ; Mei, Shaolin ; Miao, Benchun ; Sharova, Tatyana ; Alvarez-Breckenridge, Christopher ; Stocking, Jackson H. ; Kim, Tommy ; Fadden, Riley ; Lawrence, Donald ; Hoang, Mai P. ; Cahill, Daniel P. ; Malehmir, Mohsen ; Nowak, Martin A. ; Brastianos, Priscilla K. ; Lian, Christine G. ; Ruppin, Eytan ; Izar, Benjamin ; Herlyn, Meenhard ; Van Allen, Eliezer M. ; Nathanson, Katherine ; Flaherty, Keith T. ; Sullivan, Ryan J. ; Kellis, Manolis ; Sorger, Peter K. ; Boland, Genevieve M.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c540t-f2232a1efe18ad591f55dcff6688fefc6fb02f57ecfb7b7e0baf423e561ddb363</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2021</creationdate><topic>631/67/1059/2325</topic><topic>631/67/1059/2326</topic><topic>631/67/1813/1634</topic><topic>631/67/69</topic><topic>Autopsies</topic><topic>Autopsy</topic><topic>B7-H1 Antigen - antagonists &amp; inhibitors</topic><topic>B7-H1 Antigen - genetics</topic><topic>B7-H1 Antigen - immunology</topic><topic>Biochemistry &amp; Molecular Biology</topic><topic>Biomedical and Life Sciences</topic><topic>Biomedicine</topic><topic>Cancer Research</topic><topic>Cell Biology</topic><topic>Chromosome 15</topic><topic>Chromosomes, Human, Pair 15 - genetics</topic><topic>Coevolution</topic><topic>Drug Resistance, Neoplasm - drug effects</topic><topic>Evolution</topic><topic>Female</topic><topic>Gene Expression Regulation, Neoplastic</topic><topic>Gene sequencing</topic><topic>Genetic analysis</topic><topic>Humans</topic><topic>Immune checkpoint inhibitors</topic><topic>Immune Checkpoint Inhibitors - adverse effects</topic><topic>Immune Checkpoint Inhibitors - therapeutic use</topic><topic>Immune system</topic><topic>Immunofluorescence</topic><topic>Immunotherapy</topic><topic>Immunotherapy - adverse effects</topic><topic>Infectious Diseases</topic><topic>Letter</topic><topic>Life Sciences &amp; Biomedicine</topic><topic>Male</topic><topic>Medicine, Research &amp; Experimental</topic><topic>Melanoma</topic><topic>Melanoma - genetics</topic><topic>Melanoma - immunology</topic><topic>Melanoma - pathology</topic><topic>Melanoma - therapy</topic><topic>Metabolic Diseases</topic><topic>Metastases</topic><topic>Microenvironments</topic><topic>Mimicry</topic><topic>Molecular Medicine</topic><topic>Neoplasm Metastasis</topic><topic>Neoplasm Recurrence, Local - genetics</topic><topic>Neoplasm Recurrence, Local - immunology</topic><topic>Neoplasm Recurrence, Local - pathology</topic><topic>Neoplasm Recurrence, Local - therapy</topic><topic>Nerve growth factor receptors</topic><topic>Nerve Tissue Proteins - genetics</topic><topic>Nerve Tissue Proteins - immunology</topic><topic>Neurosciences</topic><topic>Patients</topic><topic>PD-L1 protein</topic><topic>Phenotypes</topic><topic>Phylogeny</topic><topic>Polarity</topic><topic>Receptors, Nerve Growth Factor - genetics</topic><topic>Receptors, Nerve Growth Factor - immunology</topic><topic>Research &amp; Experimental Medicine</topic><topic>Science &amp; Technology</topic><topic>Tumor cells</topic><topic>Tumor microenvironment</topic><topic>Tumor Microenvironment - drug effects</topic><topic>Tumors</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Liu, David</creatorcontrib><creatorcontrib>Lin, Jia-Ren</creatorcontrib><creatorcontrib>Robitschek, Emily J.</creatorcontrib><creatorcontrib>Kasumova, Gyulnara G.</creatorcontrib><creatorcontrib>Heyde, Alex</creatorcontrib><creatorcontrib>Shi, Alvin</creatorcontrib><creatorcontrib>Kraya, Adam</creatorcontrib><creatorcontrib>Zhang, Gao</creatorcontrib><creatorcontrib>Moll, Tabea</creatorcontrib><creatorcontrib>Frederick, Dennie T.</creatorcontrib><creatorcontrib>Chen, Yu-An</creatorcontrib><creatorcontrib>Wang, Shu</creatorcontrib><creatorcontrib>Schapiro, Denis</creatorcontrib><creatorcontrib>Ho, Li-Lun</creatorcontrib><creatorcontrib>Bi, Kevin</creatorcontrib><creatorcontrib>Sahu, Avinash</creatorcontrib><creatorcontrib>Mei, Shaolin</creatorcontrib><creatorcontrib>Miao, Benchun</creatorcontrib><creatorcontrib>Sharova, Tatyana</creatorcontrib><creatorcontrib>Alvarez-Breckenridge, Christopher</creatorcontrib><creatorcontrib>Stocking, Jackson H.</creatorcontrib><creatorcontrib>Kim, Tommy</creatorcontrib><creatorcontrib>Fadden, Riley</creatorcontrib><creatorcontrib>Lawrence, Donald</creatorcontrib><creatorcontrib>Hoang, Mai P.</creatorcontrib><creatorcontrib>Cahill, Daniel P.</creatorcontrib><creatorcontrib>Malehmir, Mohsen</creatorcontrib><creatorcontrib>Nowak, Martin A.</creatorcontrib><creatorcontrib>Brastianos, Priscilla K.</creatorcontrib><creatorcontrib>Lian, Christine G.</creatorcontrib><creatorcontrib>Ruppin, Eytan</creatorcontrib><creatorcontrib>Izar, Benjamin</creatorcontrib><creatorcontrib>Herlyn, Meenhard</creatorcontrib><creatorcontrib>Van Allen, Eliezer M.</creatorcontrib><creatorcontrib>Nathanson, Katherine</creatorcontrib><creatorcontrib>Flaherty, Keith T.</creatorcontrib><creatorcontrib>Sullivan, Ryan J.</creatorcontrib><creatorcontrib>Kellis, Manolis</creatorcontrib><creatorcontrib>Sorger, Peter K.</creatorcontrib><creatorcontrib>Boland, Genevieve M.</creatorcontrib><collection>Web of Science Core Collection</collection><collection>Science Citation Index Expanded</collection><collection>Web of Science - Science Citation Index Expanded - 2021</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Animal Behavior Abstracts</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Calcium &amp; 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 &amp; 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 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 &amp; Medical Complete (Alumni)</collection><collection>ProQuest Biological Science Collection</collection><collection>Health &amp; 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><collection>PubMed Central (Full Participant titles)</collection><jtitle>Nature medicine</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Liu, David</au><au>Lin, Jia-Ren</au><au>Robitschek, Emily J.</au><au>Kasumova, Gyulnara G.</au><au>Heyde, Alex</au><au>Shi, Alvin</au><au>Kraya, Adam</au><au>Zhang, Gao</au><au>Moll, Tabea</au><au>Frederick, Dennie T.</au><au>Chen, Yu-An</au><au>Wang, Shu</au><au>Schapiro, Denis</au><au>Ho, Li-Lun</au><au>Bi, Kevin</au><au>Sahu, Avinash</au><au>Mei, Shaolin</au><au>Miao, Benchun</au><au>Sharova, Tatyana</au><au>Alvarez-Breckenridge, Christopher</au><au>Stocking, Jackson H.</au><au>Kim, Tommy</au><au>Fadden, Riley</au><au>Lawrence, Donald</au><au>Hoang, Mai P.</au><au>Cahill, Daniel P.</au><au>Malehmir, Mohsen</au><au>Nowak, Martin A.</au><au>Brastianos, Priscilla K.</au><au>Lian, Christine G.</au><au>Ruppin, Eytan</au><au>Izar, Benjamin</au><au>Herlyn, Meenhard</au><au>Van Allen, Eliezer M.</au><au>Nathanson, Katherine</au><au>Flaherty, Keith T.</au><au>Sullivan, Ryan J.</au><au>Kellis, Manolis</au><au>Sorger, Peter K.</au><au>Boland, Genevieve M.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Evolution of delayed resistance to immunotherapy in a melanoma responder</atitle><jtitle>Nature medicine</jtitle><stitle>Nat Med</stitle><stitle>NAT MED</stitle><addtitle>Nat Med</addtitle><date>2021-06-01</date><risdate>2021</risdate><volume>27</volume><issue>6</issue><spage>985</spage><epage>992</epage><pages>985-992</pages><issn>1078-8956</issn><issn>1546-170X</issn><eissn>1546-170X</eissn><abstract>Despite initial responses 1 – 3 , most melanoma patients develop resistance 4 to immune checkpoint blockade (ICB). To understand the evolution of resistance, we studied 37 tumor samples over 9 years from a patient with metastatic melanoma with complete clinical response to ICB followed by delayed recurrence and death. Phylogenetic analysis revealed co-evolution of seven lineages with multiple convergent, but independent resistance-associated alterations. All recurrent tumors emerged from a lineage characterized by loss of chromosome 15q, with post-treatment clones acquiring additional genomic driver events. Deconvolution of bulk RNA sequencing and highly multiplexed immunofluorescence (t-CyCIF) revealed differences in immune composition among different lineages. Imaging revealed a vasculogenic mimicry phenotype in NGFR hi tumor cells with high PD-L1 expression in close proximity to immune cells. Rapid autopsy demonstrated two distinct NGFR spatial patterns with high polarity and proximity to immune cells in subcutaneous tumors versus a diffuse spatial pattern in lung tumors, suggesting different roles of this neural-crest-like program in different tumor microenvironments. Broadly, this study establishes a high-resolution map of the evolutionary dynamics of resistance to ICB, characterizes a de-differentiated neural-crest tumor population in melanoma immunotherapy resistance and describes site-specific differences in tumor–immune interactions via longitudinal analysis of a patient with melanoma with an unusual clinical course. Genetic and protein expression analyses of serially collected tumor biopsies from a patient with melanoma treated with immune checkpoint inhibitors provide insights into tumor microenvironment changes that occur during treatment resistance.</abstract><cop>New York</cop><pub>Nature Publishing Group US</pub><pmid>33941922</pmid><doi>10.1038/s41591-021-01331-8</doi><tpages>8</tpages><orcidid>https://orcid.org/0000-0001-5344-6645</orcidid><orcidid>https://orcid.org/0000-0002-7862-3940</orcidid><orcidid>https://orcid.org/0000-0002-7522-6173</orcidid><orcidid>https://orcid.org/0000-0001-7228-4696</orcidid><orcidid>https://orcid.org/0000-0003-2759-2125</orcidid><orcidid>https://orcid.org/0000-0002-6740-0901</orcidid><orcidid>https://orcid.org/0000-0001-5489-0908</orcidid><orcidid>https://orcid.org/0000-0002-0201-4444</orcidid><orcidid>https://orcid.org/0000-0002-9391-5722</orcidid><orcidid>https://orcid.org/0000-0002-1406-7981</orcidid><orcidid>https://orcid.org/0000-0001-6915-5850</orcidid><orcidid>https://orcid.org/0000-0003-2379-6702</orcidid><orcidid>https://orcid.org/0000-0002-3364-1838</orcidid><orcidid>https://orcid.org/0000-0003-0839-0739</orcidid><orcidid>https://orcid.org/0000-0001-7113-9630</orcidid><orcidid>https://orcid.org/0000-0003-4702-7705</orcidid><orcidid>https://orcid.org/0000-0003-4470-8425</orcidid><orcidid>https://orcid.org/0000-0002-2771-0155</orcidid><orcidid>https://orcid.org/0000-0003-0346-5033</orcidid><orcidid>https://orcid.org/0000-0002-1178-1143</orcidid><orcidid>https://orcid.org/0000-0002-2193-764X</orcidid><oa>free_for_read</oa></addata></record>
fulltext fulltext
identifier ISSN: 1078-8956
ispartof Nature medicine, 2021-06, Vol.27 (6), p.985-992
issn 1078-8956
1546-170X
1546-170X
language eng
recordid cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_8474080
source MEDLINE; Nature; Web of Science - Science Citation Index Expanded - 2021<img src="https://exlibris-pub.s3.amazonaws.com/fromwos-v2.jpg" />; Alma/SFX Local Collection
subjects 631/67/1059/2325
631/67/1059/2326
631/67/1813/1634
631/67/69
Autopsies
Autopsy
B7-H1 Antigen - antagonists & inhibitors
B7-H1 Antigen - genetics
B7-H1 Antigen - immunology
Biochemistry & Molecular Biology
Biomedical and Life Sciences
Biomedicine
Cancer Research
Cell Biology
Chromosome 15
Chromosomes, Human, Pair 15 - genetics
Coevolution
Drug Resistance, Neoplasm - drug effects
Evolution
Female
Gene Expression Regulation, Neoplastic
Gene sequencing
Genetic analysis
Humans
Immune checkpoint inhibitors
Immune Checkpoint Inhibitors - adverse effects
Immune Checkpoint Inhibitors - therapeutic use
Immune system
Immunofluorescence
Immunotherapy
Immunotherapy - adverse effects
Infectious Diseases
Letter
Life Sciences & Biomedicine
Male
Medicine, Research & Experimental
Melanoma
Melanoma - genetics
Melanoma - immunology
Melanoma - pathology
Melanoma - therapy
Metabolic Diseases
Metastases
Microenvironments
Mimicry
Molecular Medicine
Neoplasm Metastasis
Neoplasm Recurrence, Local - genetics
Neoplasm Recurrence, Local - immunology
Neoplasm Recurrence, Local - pathology
Neoplasm Recurrence, Local - therapy
Nerve growth factor receptors
Nerve Tissue Proteins - genetics
Nerve Tissue Proteins - immunology
Neurosciences
Patients
PD-L1 protein
Phenotypes
Phylogeny
Polarity
Receptors, Nerve Growth Factor - genetics
Receptors, Nerve Growth Factor - immunology
Research & Experimental Medicine
Science & Technology
Tumor cells
Tumor microenvironment
Tumor Microenvironment - drug effects
Tumors
title Evolution of delayed resistance to immunotherapy in a melanoma responder
url https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-12-05T18%3A50%3A16IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Evolution%20of%20delayed%20resistance%20to%20immunotherapy%20in%20a%20melanoma%20responder&rft.jtitle=Nature%20medicine&rft.au=Liu,%20David&rft.date=2021-06-01&rft.volume=27&rft.issue=6&rft.spage=985&rft.epage=992&rft.pages=985-992&rft.issn=1078-8956&rft.eissn=1546-170X&rft_id=info:doi/10.1038/s41591-021-01331-8&rft_dat=%3Cproquest_pubme%3E2522191767%3C/proquest_pubme%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2541123273&rft_id=info:pmid/33941922&rfr_iscdi=true