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Evolution of delayed resistance to immunotherapy in a melanoma responder.
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.
Afiliación
  • Liu D; Dana-Farber Cancer Institute, Boston, MA, USA.
  • Lin JR; Broad Institute of Harvard and MIT, Cambridge, MA, USA.
  • Robitschek EJ; Laboratory of Systems Pharmacology, Harvard Medical School, Boston, MA, USA.
  • Kasumova GG; Dana-Farber Cancer Institute, Boston, MA, USA.
  • Heyde A; Broad Institute of Harvard and MIT, Cambridge, MA, USA.
  • Shi A; Division of Surgical Oncology, Department of Surgery, Massachusetts General Hospital, Boston, MA, USA.
  • Kraya A; Program for Evolutionary Dynamics, Harvard University, Cambridge, MA, USA.
  • Zhang G; Department of Organismic and Evolutionary Biology, Harvard University, Cambridge, MA, USA.
  • Moll T; Broad Institute of Harvard and MIT, Cambridge, MA, USA.
  • Frederick DT; Computer Science and Artificial Intelligence Lab, Massachusetts Institute of Technology, Cambridge, MA, USA.
  • Chen YA; Division of Translational Medicine and Human Genetics, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
  • Wang S; Molecular and Cellular Oncogenesis Program, The Wistar Institute, Philadelphia, PA, USA.
  • Schapiro D; Preston Robert Tisch Brain Tumor Center, Department of Neurosurgery, Department of Pathology, Duke University School of Medicine, Durham, NC, USA.
  • Ho LL; Division of Medical Oncology, Department of Medicine, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA, USA.
  • Bi K; Division of Medical Oncology, Department of Medicine, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA, USA.
  • Sahu A; Laboratory of Systems Pharmacology, Harvard Medical School, Boston, MA, USA.
  • Mei S; Laboratory of Systems Pharmacology, Harvard Medical School, Boston, MA, USA.
  • Miao B; Laboratory of Systems Pharmacology, Harvard Medical School, Boston, MA, USA.
  • Sharova T; Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Alvarez-Breckenridge C; Broad Institute of Harvard and MIT, Cambridge, MA, USA.
  • Stocking JH; Computer Science and Artificial Intelligence Lab, Massachusetts Institute of Technology, Cambridge, MA, USA.
  • Kim T; Dana-Farber Cancer Institute, Boston, MA, USA.
  • Fadden R; Broad Institute of Harvard and MIT, Cambridge, MA, USA.
  • Lawrence D; Dana-Farber Cancer Institute, Boston, MA, USA.
  • Hoang MP; Dana-Farber Cancer Institute, Boston, MA, USA.
  • Cahill DP; Laboratory of Systems Pharmacology, Harvard Medical School, Boston, MA, USA.
  • Malehmir M; Division of Medical Oncology, Department of Medicine, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA, USA.
  • Nowak MA; Division of Surgical Oncology, Department of Surgery, Massachusetts General Hospital, Boston, MA, USA.
  • Brastianos PK; Department of Neurosurgery, Harvard Medical School, Massachusetts General Hospital, Boston, MA, USA.
  • Lian CG; Division of Medical Oncology, Department of Medicine, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA, USA.
  • Ruppin E; Division of Surgical Oncology, Department of Surgery, Massachusetts General Hospital, Boston, MA, USA.
  • Izar B; Division of Medical Oncology, Department of Medicine, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA, USA.
  • Herlyn M; Division of Medical Oncology, Department of Medicine, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA, USA.
  • Van Allen EM; Department of Pathology, Harvard Medical School, Massachusetts General Hospital, Boston, MA, USA.
  • Nathanson K; Department of Neurosurgery, Harvard Medical School, Massachusetts General Hospital, Boston, MA, USA.
  • Flaherty KT; Broad Institute of Harvard and MIT, Cambridge, MA, USA.
  • Sullivan RJ; Division of Surgical Oncology, Department of Surgery, Massachusetts General Hospital, Boston, MA, USA.
  • Kellis M; Program for Evolutionary Dynamics, Harvard University, Cambridge, MA, USA.
  • Sorger PK; Department of Organismic and Evolutionary Biology, Harvard University, Cambridge, MA, USA.
  • Boland GM; Department of Mathematics, Harvard University, Cambridge, MA, USA.
Nat Med ; 27(6): 985-992, 2021 06.
Article en En | MEDLINE | ID: mdl-33941922
ABSTRACT
Despite 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.
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Texto completo: 1 Banco de datos: MEDLINE Asunto principal: Receptores de Factor de Crecimiento Nervioso / Antígeno B7-H1 / Inhibidores de Puntos de Control Inmunológico / Melanoma / Proteínas del Tejido Nervioso Límite: Female / Humans / Male Idioma: En Año: 2021 Tipo del documento: Article
Texto completo
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Texto completo: 1 Banco de datos: MEDLINE Asunto principal: Receptores de Factor de Crecimiento Nervioso / Antígeno B7-H1 / Inhibidores de Puntos de Control Inmunológico / Melanoma / Proteínas del Tejido Nervioso Límite: Female / Humans / Male Idioma: En Año: 2021 Tipo del documento: Article