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...
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Veröffentlicht in: | Nature medicine 2021-06, Vol.27 (6), p.985-992 |
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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 |
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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 & inhibitors</subject><subject>B7-H1 Antigen - genetics</subject><subject>B7-H1 Antigen - immunology</subject><subject>Biochemistry & 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 & Biomedicine</subject><subject>Male</subject><subject>Medicine, Research & 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 & Experimental Medicine</subject><subject>Science & Technology</subject><subject>Tumor cells</subject><subject>Tumor microenvironment</subject><subject>Tumor Microenvironment - drug 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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 & inhibitors</topic><topic>B7-H1 Antigen - genetics</topic><topic>B7-H1 Antigen - immunology</topic><topic>Biochemistry & 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 & Biomedicine</topic><topic>Male</topic><topic>Medicine, Research & 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 & Experimental Medicine</topic><topic>Science & 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 & 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 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(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> |
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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 |
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