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

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...

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Bibliographic Details
Published in:Cell Vol. 167; no. 6; p. 1540
Main Authors: Benci, Joseph L, Xu, Bihui, Qiu, Yu, Wu, Tony J, Dada, Hannah, Twyman-Saint Victor, Christina, Cucolo, Lisa, Lee, David S M, Pauken, Kristen E, Huang, Alexander C, Gangadhar, Tara C, Amaravadi, Ravi K, Schuchter, Lynn M, Feldman, Michael D, Ishwaran, Hemant, Vonderheide, Robert H, Maity, Amit, Wherry, E John, Minn, Andy J
Format: Journal Article
Language:English
Published: United States 01.12.2016
Subjects:
Animals
B7-H1 Antigen - metabolism
Cell Line, Tumor
CTLA-4 Antigen - antagonists & inhibitors
Drug Resistance, Neoplasm
Heterografts
Humans
Interferons - immunology
Melanoma - drug therapy
Melanoma - immunology
Melanoma - radiotherapy
Melanoma - therapy
Mice
Neoplasm Transplantation
Radioimmunotherapy
STAT1 Transcription Factor
T-Lymphocytes - immunology
ISSN:1097-4172, 1097-4172
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Summary: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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ISSN:1097-4172
1097-4172
DOI:10.1016/j.cell.2016.11.022