Transcriptional mechanisms of resistance to anti-PD-1 therapy

Maria L. Ascierto, Alvin Makohon-Moore, Evan J. Lipson, Janis M. Taube, Tracee L. McMiller, Alan E. Berger, Jinshui Fan, Genevieve J. Kaunitz, Tricia R. Cottrell, Zachary A. Kohutek, Alexander Favorov, Vladimir Makarov, Nadeem Riaz, Timothy A. Chan, Leslie Cope, Ralph H. Hruban, Drew M. Pardoll, Barry S. Taylor, David B. Solit, Christine Iacobuzio-DonahueSuzanne L. Topalian

Research output: Contribution to journalArticle

Abstract

Purpose: To explore factors associated with response and resistance to anti-PD-1 therapy, we analyzed multiple disease sites at autopsy in a patient with widely metastatic melanoma who had a heterogeneous response. Materials and Methods: Twenty-six melanoma specimens (four premortem, 22 postmortem) were subjected to whole exome sequencing. Candidate immunologic markers and gene expression were assessed in 10 cutaneous metastases showing response or progression during therapy. Results: The melanoma was driven by biallelic inactivation of NF1. All lesions had highly concordant mutational profiles and copy number alterations, indicating linear clonal evolution. Expression of candidate immunologic markers was similar in responding and progressing lesions. However, progressing cutaneous metastases were associated with overexpression of genes associated with extracellular matrix and neutrophil function. Conclusions: Although mutational and immunologic differences have been proposed as the primary determinants of heterogeneous response/resistance to targeted therapies and immunotherapies, respectively, differential lesional gene expression profiles may also dictate anti-PD-1 outcomes.

Original languageEnglish (US)
Pages (from-to)3168-3180
Number of pages13
JournalClinical Cancer Research
Volume23
Issue number12
DOIs
StatePublished - Jun 15 2017

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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  • Cite this

    Ascierto, M. L., Makohon-Moore, A., Lipson, E. J., Taube, J. M., McMiller, T. L., Berger, A. E., Fan, J., Kaunitz, G. J., Cottrell, T. R., Kohutek, Z. A., Favorov, A., Makarov, V., Riaz, N., Chan, T. A., Cope, L., Hruban, R. H., Pardoll, D. M., Taylor, B. S., Solit, D. B., ... Topalian, S. L. (2017). Transcriptional mechanisms of resistance to anti-PD-1 therapy. Clinical Cancer Research, 23(12), 3168-3180. https://doi.org/10.1158/1078-0432.CCR-17-0270