Tumor Interferon Signaling Regulates a Multigenic Resistance Program to Immune Checkpoint Blockade

Joseph L. Benci, Bihui Xu, Yu Qiu, Tony J. Wu, Hannah Dada, Christina Twyman-Saint Victor, Lisa Cucolo, David S.M. Lee, Kristen E. Pauken, Alexander C. Huang, Tara C. Gangadhar, Ravi K. Amaravadi, Lynn M. Schuchter, Michael D. Feldman, Hemant Ishwaran, Robert H. Vonderheide, Amit Maity, E. John Wherry, Andy J. Minn

Research output: Contribution to journalArticle

308 Scopus citations

Abstract

Therapeutic blocking of the PD1 pathway results in significant tumor responses, but resistance is common. We demonstrate that prolonged interferon signaling orchestrates PDL1-dependent and PDL1-independent resistance to immune checkpoint blockade (ICB) and to combinations such as radiation plus anti-CTLA4. Persistent type II interferon signaling allows tumors to acquire STAT1-related epigenomic changes and augments expression of interferon-stimulated genes and ligands for multiple T cell inhibitory receptors. Both type I and II interferons maintain this resistance program. Crippling the program genetically or pharmacologically interferes with multiple inhibitory pathways and expands distinct T cell populations with improved function despite expressing markers of severe exhaustion. Consequently, tumors resistant to multi-agent ICB are rendered responsive to ICB monotherapy. Finally, we observe that biomarkers for interferon-driven resistance associate with clinical progression after anti-PD1 therapy. Thus, the duration of tumor interferon signaling augments adaptive resistance and inhibition of the interferon response bypasses requirements for combinatorial ICB therapies.

Original languageEnglish (US)
Pages (from-to)1540-1554.e12
JournalCell
Volume167
Issue number6
DOIs
StatePublished - Dec 1 2016

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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    Benci, J. L., Xu, B., Qiu, Y., Wu, T. J., Dada, H., Twyman-Saint Victor, C., Cucolo, L., Lee, D. S. M., Pauken, K. E., Huang, A. C., Gangadhar, T. C., Amaravadi, R. K., Schuchter, L. M., Feldman, M. D., Ishwaran, H., Vonderheide, R. H., Maity, A., Wherry, E. J., & Minn, A. J. (2016). Tumor Interferon Signaling Regulates a Multigenic Resistance Program to Immune Checkpoint Blockade. Cell, 167(6), 1540-1554.e12. https://doi.org/10.1016/j.cell.2016.11.022