TY - JOUR
T1 - Sustained Type I interferon signaling as a mechanism of resistance to PD-1 blockade
AU - Jacquelot, Nicolas
AU - Yamazaki, Takahiro
AU - Roberti, Maria P.
AU - Duong, Connie P.M.
AU - Andrews, Miles C.
AU - Verlingue, Loic
AU - Ferrere, Gladys
AU - Becharef, Sonia
AU - Vétizou, Marie
AU - Daillère, Romain
AU - Messaoudene, Meriem
AU - Enot, David P.
AU - Stoll, Gautier
AU - Ugel, Stefano
AU - Marigo, Ilaria
AU - Foong Ngiow, Shin
AU - Marabelle, Aurélien
AU - Prevost-Blondel, Armelle
AU - Gaudreau, Pierre Olivier
AU - Gopalakrishnan, Vancheswaran
AU - Eggermont, Alexander M.
AU - Opolon, Paule
AU - Klein, Christophe
AU - Madonna, Gabriele
AU - Ascierto, Paolo A.
AU - Sucker, Antje
AU - Schadendorf, Dirk
AU - Smyth, Mark J.
AU - Soria, Jean Charles
AU - Kroemer, Guido
AU - Bronte, Vincenzo
AU - Wargo, Jennifer
AU - Zitvogel, Laurence
N1 - Publisher Copyright:
© 2019, IBCB, SIBS, CAS.
PY - 2019/10/1
Y1 - 2019/10/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85072223252&partnerID=8YFLogxK
U2 - 10.1038/s41422-019-0224-x
DO - 10.1038/s41422-019-0224-x
M3 - Article
C2 - 31481761
AN - SCOPUS:85072223252
SN - 1001-0602
VL - 29
SP - 846
EP - 861
JO - Cell Research
JF - Cell Research
IS - 10
ER -