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

Cell | Dec 1, 2016

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.

Pubmed ID: 27912061 RIS Download

Mesh terms: Animals | B7-H1 Antigen | CTLA-4 Antigen | Cell Line, Tumor | Drug Resistance, Neoplasm | Heterografts | Humans | Interferons | Melanoma | Mice | Neoplasm Transplantation | Radioimmunotherapy | STAT1 Transcription Factor | T-Lymphocytes

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Associated grants

  • Agency: NCI NIH HHS, Id: R01 CA163739
  • Agency: NIAID NIH HHS, Id: U19 AI082630
  • Agency: NIAID NIH HHS, Id: P01 AI112521
  • Agency: NCI NIH HHS, Id: P50 CA174523
  • Agency: NCI NIH HHS, Id: R01 CA158186
  • Agency: NCI NIH HHS, Id: P30 CA016520
  • Agency: NIAID NIH HHS, Id: R01 AI105343
  • Agency: NIAID NIH HHS, Id: U01 AI095608
  • Agency: NCI NIH HHS, Id: R01 CA172651

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