Sustained Type I interferon signaling as a mechanism of resistance to PD-1 blockade.
Cell Res
; 29(10): 846-861, 2019 Oct.
Article
in En
| MEDLINE
| ID: mdl-31481761
ABSTRACT
PD-1 blockade represents a major therapeutic avenue in anticancer immunotherapy. Delineating mechanisms of secondary resistance to this strategy is increasingly important. Here, we identified the deleterious role of signaling via the type I interferon (IFN) receptor in tumor and antigen presenting cells, that induced the expression of nitric oxide synthase 2 (NOS2), associated with intratumor accumulation of regulatory T cells (Treg) and myeloid cells and acquired resistance to anti-PD-1 monoclonal antibody (mAb). Sustained IFNß transcription was observed in resistant tumors, in turn inducing PD-L1 and NOS2 expression in both tumor and dendritic cells (DC). Whereas PD-L1 was not involved in secondary resistance to anti-PD-1 mAb, pharmacological or genetic inhibition of NOS2 maintained long-term control of tumors by PD-1 blockade, through reduction of Treg and DC activation. Resistance to immunotherapies, including anti-PD-1 mAb in melanoma patients, was also correlated with the induction of a type I IFN signature. Hence, the role of type I IFN in response to PD-1 blockade should be revisited as sustained type I IFN signaling may contribute to resistance to therapy.
Full text:
1
Database:
MEDLINE
Main subject:
Signal Transduction
/
Interferon Type I
/
Programmed Cell Death 1 Receptor
/
Antibodies, Monoclonal
Limits:
Animals
/
Humans
Language:
En
Journal:
Cell Res
Year:
2019
Type:
Article
Affiliation country:
France