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Cancer Immunol Res. 2018 Sep 21. doi: 10.1158/2326-6066.CIR-18-0193. [Epub ahead of print]

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

Author information

1
Belfer Center for Applied Cancer Science, Boston, Massachusetts.
2
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
3
Department of Oncology, National Taiwan University Hospital, Zhongzheng District, Taipei City, Taiwan.
4
Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts.
5
Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts.
6
Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
7
Belfer Center for Applied Cancer Science, Boston, Massachusetts. Pasi_Janne@dfci.harvard.edu.

Abstract

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. Cancer Immunol Res; 1-13. ©2018 AACR.

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