Sustained Type I interferon signaling as a mechanism of resistance to PD-1 blockade

Jacquelot, N; Yamazaki, T; Roberti, MP; Duong, CPM; Andrews, MC; Verlingue, L; Ferrere, G; Becharef, S; Vetizou, M; Daillere, R; Messaoudene, M; Enot, DP; Stoll, G; Ugel, S; Marigo, I; Foong Ngiow, S; Marabelle, A; Prevost-Blondel, A; Gaudreau, PO; Gopalakrishnan, V; Eggermont, AM; Opolon, P; Klein, C; Madonna, G; Ascierto, PA; Sucker, A; Schadendorf, D; Smyth, MJ; Soria, JC; KROEMER, G; Bronte, V; Wargo, J; Zitvogel, L

Author(s): Jacquelot, N; Yamazaki, T; Roberti, MP; Duong, CPM; Andrews, MC; Verlingue, L; Ferrere, G; Becharef, S; Vetizou, M; Daillere, R; Messaoudene, M; Enot, DP; Stoll, G; Ugel, S; Marigo, I; Foong Ngiow, S; Marabelle, A; Prevost-Blondel, A; Gaudreau, PO; Gopalakrishnan, V; Eggermont, AM; Opolon, P; Klein, C; Madonna, G; Ascierto, PA; Sucker, A; Schadendorf, D; Smyth, MJ; Soria, JC; KROEMER, G; Bronte, V; Wargo, J; Zitvogel, L;
Details: Publication Year 2019-10,Volume 29,Issue #10,Page 846-861
Journal Title: Stem Cell Research
Publication Type: Journal Article
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 IFNbeta 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.
Publisher: Springer Nature
Research Division(s): Immunology
PubMed ID: 31481761
Publisher's Version: https://doi.org/10.1038/s41422-019-0224-x
Open Access at Publisher's Site: https://doi.org/10.1038/s41422-019-0224-x
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2019-09-20 10:16:32

Last Modified: 2019-10-28 11:28:34