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Article: Evolution of delayed resistance to immunotherapy in a melanoma responder

TitleEvolution of delayed resistance to immunotherapy in a melanoma responder
Authors
Issue Date2021
Citation
Nature Medicine, 2021, v. 27, n. 6, p. 985-992 How to Cite?
AbstractDespite initial responses1–3, most melanoma patients develop resistance4 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 NGFRhi 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.
Persistent Identifierhttp://hdl.handle.net/10722/318925
ISSN
2023 Impact Factor: 58.7
2023 SCImago Journal Rankings: 19.045
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorLiu, David-
dc.contributor.authorLin, Jia Ren-
dc.contributor.authorRobitschek, Emily J.-
dc.contributor.authorKasumova, Gyulnara G.-
dc.contributor.authorHeyde, Alex-
dc.contributor.authorShi, Alvin-
dc.contributor.authorKraya, Adam-
dc.contributor.authorZhang, Gao-
dc.contributor.authorMoll, Tabea-
dc.contributor.authorFrederick, Dennie T.-
dc.contributor.authorChen, Yu An-
dc.contributor.authorWang, Shu-
dc.contributor.authorSchapiro, Denis-
dc.contributor.authorHo, Li Lun-
dc.contributor.authorBi, Kevin-
dc.contributor.authorSahu, Avinash-
dc.contributor.authorMei, Shaolin-
dc.contributor.authorMiao, Benchun-
dc.contributor.authorSharova, Tatyana-
dc.contributor.authorAlvarez-Breckenridge, Christopher-
dc.contributor.authorStocking, Jackson H.-
dc.contributor.authorKim, Tommy-
dc.contributor.authorFadden, Riley-
dc.contributor.authorLawrence, Donald-
dc.contributor.authorHoang, Mai P.-
dc.contributor.authorCahill, Daniel P.-
dc.contributor.authorMalehmir, Mohsen-
dc.contributor.authorNowak, Martin A.-
dc.contributor.authorBrastianos, Priscilla K.-
dc.contributor.authorLian, Christine G.-
dc.contributor.authorRuppin, Eytan-
dc.contributor.authorIzar, Benjamin-
dc.contributor.authorHerlyn, Meenhard-
dc.contributor.authorVan Allen, Eliezer M.-
dc.contributor.authorNathanson, Katherine-
dc.contributor.authorFlaherty, Keith T.-
dc.contributor.authorSullivan, Ryan J.-
dc.contributor.authorKellis, Manolis-
dc.contributor.authorSorger, Peter K.-
dc.contributor.authorBoland, Genevieve M.-
dc.date.accessioned2022-10-11T12:24:52Z-
dc.date.available2022-10-11T12:24:52Z-
dc.date.issued2021-
dc.identifier.citationNature Medicine, 2021, v. 27, n. 6, p. 985-992-
dc.identifier.issn1078-8956-
dc.identifier.urihttp://hdl.handle.net/10722/318925-
dc.description.abstractDespite initial responses1–3, most melanoma patients develop resistance4 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 NGFRhi 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.-
dc.languageeng-
dc.relation.ispartofNature Medicine-
dc.titleEvolution of delayed resistance to immunotherapy in a melanoma responder-
dc.typeArticle-
dc.description.naturelink_to_subscribed_fulltext-
dc.identifier.doi10.1038/s41591-021-01331-8-
dc.identifier.pmid33941922-
dc.identifier.scopuseid_2-s2.0-85105326395-
dc.identifier.volume27-
dc.identifier.issue6-
dc.identifier.spage985-
dc.identifier.epage992-
dc.identifier.eissn1546-170X-
dc.identifier.isiWOS:000646516200001-

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