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

By Joseph L. Benci, Bihui Xu, Yu Qiu, Tony J. Wu, Hannah Dada, Christina Twyman-Saint Victor, Lisa Cucolo, David S. Lee, Kristen E. Pauken, Alexander C. Huang and 9 more. Cell, 2016

1,039 citations recorded by the source corpus.

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.

Subfields: Immunology, Oncology

View Paper: https://www.semanticscholar.org/paper/9b3199373f249001467c4b3f4322d3b8488efc9a

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Immunology

In Oncology

Citations in the corpus

Spatially organized multicellular immune hubs in human colorectal cancer (2021, background): “Indeed, mechanistic work in the B16 melanoma mouse model suggests that IFNg can drive a multigenic resistance program (Benci et al., 2016).”
Interferon-Gamma at the Crossroads of Tumor Immune Surveillance or Evasion (2018, background): “Prolonged IFN-γ signaling in tumors was also shown to coordinate PD-L1-dependent and PD-L1-independent resistance to immune checkpoint blockade and to other therapeutic combinations, such as radiation and anti-CTLA-4, through a multigenic resistance program (259).”
T Cell Dysfunction in Cancer (2018, background): “However, support for the former model comes from work that assessed resistance to CTLA-4 blockade and radiation in a murine melanoma model (Benci et al., 2016).”
Interrogation of the Microenvironmental Landscape in Brain Tumors Reveals Disease-Specific Alterations of Immune Cells (2020, background): “Sustained type I IFN signaling has been implicated in mediating immune suppression and ICB resistance (Benci et al., 2016).”
Mechanisms of resistance to immune checkpoint inhibitors (2018, background): “…pre-clinical observation in an immune-competent melanoma model is that acquired resistance to ICI blockade could be overcome by inhibiting JAK1/JAK2 signalling, suggesting that JAK/STAT signalling may have a more complex role in mediating response and resistance to ICI (Benci et al, 2016).”