Tumor interferon signaling regulates a multigenic resistance program to immune checkpoint blockade

• Joseph L. Benci ^[1] ; Bihui Xu ^[1] ; Yu Qiu ^[1]
  1. [1] University of Pennsylvania

     University of Pennsylvania

     City of Philadelphia, Estados Unidos

     
• Localización: Cell, ISSN 0092-8674, Vol. 167, Nº. 6, 2016, págs. 1540-1554
• Idioma: inglés
• Texto completo no disponible (Saber más ...)
• Resumen

  • 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.