학술논문
Sustained Type I interferon signaling as a mechanism of resistance to PD-1 blockade
Document Type
Article
Author
Jacquelot, Nicolas; Yamazaki, Takahiro; Roberti, Maria P.; Duong, Connie P. M.; Andrews, Miles C.; Verlingue, Loic; Ferrere, Gladys; Becharef, Sonia; Vétizou, Marie; Daillère, Romain; Messaoudene, Meriem; Enot, David P.; Stoll, Gautier; Ugel, Stefano; Marigo, Ilaria; Foong Ngiow, Shin; Marabelle, Aurélien; Prevost-Blondel, Armelle; Gaudreau, Pierre-Olivier; Gopalakrishnan, Vancheswaran; Eggermont, Alexander M.; Opolon, Paule; Klein, Christophe; Madonna, Gabriele; Ascierto, Paolo A.; Sucker, Antje; Schadendorf, Dirk; Smyth, Mark J.; Soria, Jean-Charles; Kroemer, Guido; Bronte, Vincenzo; Wargo, Jennifer; Zitvogel, Laurence
Source
Cell Research; October 2019, Vol. 29 Issue: 10 p846-861, 16p
Subject
Language
ISSN
10010602; 17487838
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 IFNβ 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.