A High-Throughput Immune-Oncology Screen Identifies EGFR Inhibitors as Potent Enhancers of Antigen-Specific Cytotoxic T-lymphocyte Tumor Cell Killing

  • Patrick H. Lizotte
    1Belfer Center for Applied Cancer Science, Boston, Massachusetts.
  • Ruey-Long Hong
    3Department of Oncology, National Taiwan University Hospital, Zhongzheng District, Taipei City, Taiwan.
  • Troy A. Luster
    1Belfer Center for Applied Cancer Science, Boston, Massachusetts.
  • Megan E. Cavanaugh
    1Belfer Center for Applied Cancer Science, Boston, Massachusetts.
  • Luke J. Taus
    1Belfer Center for Applied Cancer Science, Boston, Massachusetts.
  • Stephen Wang
    1Belfer Center for Applied Cancer Science, Boston, Massachusetts.
  • Abha Dhaneshwar
    1Belfer Center for Applied Cancer Science, Boston, Massachusetts.
  • Naomi Mayman
    1Belfer Center for Applied Cancer Science, Boston, Massachusetts.
  • Aaron Yang
    1Belfer Center for Applied Cancer Science, Boston, Massachusetts.
  • Meghana Kulkarni
    1Belfer Center for Applied Cancer Science, Boston, Massachusetts.
  • Lauren Badalucco
    1Belfer Center for Applied Cancer Science, Boston, Massachusetts.
  • Erica Fitzpatrick
    1Belfer Center for Applied Cancer Science, Boston, Massachusetts.
  • Hsiang-Fong Kao
    3Department of Oncology, National Taiwan University Hospital, Zhongzheng District, Taipei City, Taiwan.
  • Mari Kuraguchi
    1Belfer Center for Applied Cancer Science, Boston, Massachusetts.
  • Mark Bittinger
    1Belfer Center for Applied Cancer Science, Boston, Massachusetts.
  • Paul T. Kirschmeier
    1Belfer Center for Applied Cancer Science, Boston, Massachusetts.
  • Nathanael S. Gray
    4Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts.
  • David A. Barbie
    1Belfer Center for Applied Cancer Science, Boston, Massachusetts.
  • Pasi A. Jänne
    1Belfer Center for Applied Cancer Science, Boston, Massachusetts.

抄録

<jats:title>Abstract</jats:title> <jats:p>We developed a screening assay in which luciferized ID8 expressing OVA was cocultured with transgenic CD8+ T cells specifically recognizing the model antigen in an H-2b–restricted manner. The assay was screened with a small-molecule library to identify compounds that inhibit or enhance T cell–mediated killing of tumor cells. Erlotinib, an EGFR inhibitor, was the top compound that enhanced T-cell killing of tumor cells. Subsequent experiments with erlotinib and additional EGFR inhibitors validated the screen results. EGFR inhibitors increased both basal and IFNγ-induced MHC class-I presentation, which enhanced recognition and lysis of tumor cell targets by CD8+ cytotoxic T lymphocytes. The ID8 cell line was also transduced to constitutively express Cas9, and a pooled CRISPR screen, utilizing the same target tumor cell/T-cell assay, identified single-guide (sg)RNAs targeting EGFR that sensitized tumor cells to T cell–mediated killing. Combination of PD-1 blockade with EGFR inhibition showed significant synergistic efficacy in a syngeneic model, further validating EGFR inhibitors as immunomodulatory agents that enhance checkpoint blockade. This assay can be screened in high-throughput with small-molecule libraries and genome-wide CRISPR/Cas9 libraries to identify both compounds and target genes, respectively, that enhance or inhibit T-cell recognition and killing of tumor cells. Retrospective analyses of squamous-cell head and neck cancer (SCCHN) patients treated with the combination of afatinib and pembrolizumab demonstrated a rate of clinical activity exceeding that of each single agent. Prospective clinical trials evaluating the combination of an EGFR inhibitor and PD-1 blockade should be conducted.</jats:p>

収録刊行物

  • Cancer Immunology Research

    Cancer Immunology Research 6 (12), 1511-1523, 2018-12-01

    American Association for Cancer Research (AACR)

被引用文献 (1)*注記

もっと見る

詳細情報 詳細情報について

問題の指摘

ページトップへ