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Multimodel preclinical platform predicts clinical response of melanoma to immunotherapy

  1. Author:
    Pérez-Guijarro, Eva [ORCID]
    Yang, Howard H
    Araya, Romina E
    El Meskini,Rajaa
    Michael, Helen T
    Vodnala, Suman Kumar
    Marie, Kerrie L
    Smith,Cari
    Chin, Sung
    Lam, Khiem C
    Thorkelsson, Andres
    Iacovelli,Anthony
    Kulaga,Alan
    Fon, Anyen
    Michalowski, Aleksandra M
    Hugo, Willy
    Lo, Roger S
    Restifo, Nicholas P
    Sharan,Shyam [ORCID]
    Van Dyke, Terry
    Goldszmid, Romina S
    Ohler,Zoe [ORCID]
    Lee, Maxwell P [ORCID]
    Day, Chi-Ping [ORCID]
    Merlino, Glenn [ORCID]

  2. Author Address

    Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA., Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA., Center for Advanced Preclinical Research, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD, USA., Surgery Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA., Lyell Immunopharma, South San Francisco, CA, USA., Laboratory Animal Science Program, Leidos Biomedical Research Inc, Frederick, MD, USA., Division of Dermatology, Department of Medicine, University of California, Los Angeles, Los Angeles, CA, USA., Mouse Cancer Genetics Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD, USA., Path Forward Solutions, Frederick, MD, USA., Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. leemax@mail.nih.gov., Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. chi-ping.day@nih.gov., Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. gmerlino@helix.nih.gov.,
    1. Year: 2020
    2. Date: Apr 13
    3. Epub Date: 2020 04 13
  2. Journal: Nature medicine
  4. Type of Article: Article
  5. ISSN: 1078-8956
  1. Abstract:

    Although immunotherapy has revolutionized cancer treatment, only a subset of patients demonstrate durable clinical benefit. Definitive predictive biomarkers and targets to overcome resistance remain unidentified, underscoring the urgency to develop reliable immunocompetent models for mechanistic assessment. Here we characterize a panel of syngeneic mouse models, representing a variety of molecular and phenotypic subtypes of human melanomas and exhibiting their diverse range of responses to immune checkpoint blockade (ICB). Comparative analysis of genomic, transcriptomic and tumor-infiltrating immune cell profiles demonstrated alignment with clinical observations and validated the correlation of T cell dysfunction and exclusion programs with resistance. Notably, genome-wide expression analysis uncovered a melanocytic plasticity signature predictive of patient outcome in response to ICB, suggesting that the multipotency and differentiation status of melanoma can determine ICB benefit. Our comparative preclinical platform recapitulates melanoma clinical behavior and can be employed to identify mechanisms and treatment strategies to improve patient care.

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External Sources

  1. View Full Text
  2. DOI: 10.1038/s41591-020-0818-3
  3. PMID: 32284588
  4. View record in Web of Science®
  5. WOS: 000526266600002
  6. PII : 10.1038/s41591-020-0818-3

Library Notes

  1. Fiscal Year: FY2019-2020
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