Tumor Interferon Signaling Regulates a Multigenic Resistance Program to Immune Checkpoint Blockade
| Autor: | Lisa Cucolo, David Lee, Tony J. Wu, Robert H. Vonderheide, Hannah Dada, Bihui Xu, Lynn M. Schuchter, Tara C. Gangadhar, Christina Twyman-Saint Victor, Michael Feldman, E. John Wherry, Yu Qiu, Kristen E. Pauken, Andy J. Minn, Joseph L. Benci, Hemant Ishwaran, Amit Maity, Alexander C. Huang, Ravi K. Amaravadi |
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| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
T-Lymphocytes T cell Programmed Cell Death 1 Receptor Drug resistance Biology General Biochemistry Genetics and Molecular Biology Article B7-H1 Antigen Mice 03 medical and health sciences Interferon Cell Line Tumor Neoplasms medicine Animals Neoplasm Humans CTLA-4 Antigen Melanoma Epigenomics Antibodies Monoclonal Radioimmunotherapy medicine.disease Immune checkpoint Blockade STAT1 Transcription Factor 030104 developmental biology medicine.anatomical_structure Drug Resistance Neoplasm Cell culture Immunology Cancer research Heterografts Interferons Immunotherapy Neoplasm Transplantation medicine.drug |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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