期刊
CELL
卷 167, 期 6, 页码 1540-+出版社
CELL PRESS
DOI: 10.1016/j.cell.2016.11.022
关键词
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资金
- Melanoma Research Alliance
- Parker Institute for Cancer Immunotherapy
- Robertson Foundation/Cancer Research Institute Irvington Fellowship
- NIH [P50CA174523, R01CA163739, R01CA158186, P30CA016520, U19AI082630, R01AI105343, U01AI095608, P01AI112521]
- Basser Research Center for BRCA
- Abramson Cancer Center Translational Center of Excellence in Pancreatic Cancer
- NIH/NCI [R01CA172651]
- Merck
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.
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