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

Nicolas Jacquelot,Marie Vétizou,Aurélien Marabelle,Romain Daillère,Gautier Stoll,Alexander M.m Eggermont ,Mark J Smyth,Takahiro Yamazaki,Armelle Prévost-Blondel ,Shin Foong Ngiow,Paule Opolon,Jean Charles Soria ,Stefano Ugel,María Paula Roberti ,Vincenzo Bronte,Vancheswaran Gopalakrishnan,Miles C Andrews,Dirk Schadendorf,Pierre Olivier Gaudreau ,Antje Sucker,Christophe Klein,Paolo A Ascierto,Jennifer A Wargo ,Ilaria Marigo,Gabriele Madonna,David Enot ,Connie P.m Duong ,Sonia Becharef,Meriem Messaoudene,Loïc Verlingue ,Guido Kroemer,Gladys Ferrere,Laurence Zitvogel

doi:10.1038/s41422-019-0224-x

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.

Highlights

While the MCA205WT sarcoma remained sensitive to 4 doses of Programmed cell death 1 (PD-1) blockade over 12 days (Fig. 1b; Supplementary information, Fig. S1b), hosts bearing MCA205OVA and MC38 colon cancers were eventually resistant as initial treatments slightly reduced their tumor growth kinetics (Fig. 1c; Supplementary information, Fig. S1a, c and e)
Whilst tumor growth in the sensitive (MCA205WT) model displayed a rebound after the period of active anti-PD-1 therapy, we showed that prolonging the administration of anti-PD-1 monoclonal antibody (mAb) from 4 to 6 doses failed to extend the efficacy of therapy, culminating in overt tumor progression in the majority of animals (Fig. 1e, f; Supplementary information, Fig. S1f)
By studying various tumor models exhibiting phenotypic traits of reduced, early or late resistance to a therapeutic antibody inhibiting the PD-1 immune checkpoint, we have unraveled IFNAR-induced nitric oxide synthase 2 (NOS2) expression as a critical negative regulator of sustained anti-cancer efficacy of the PD-1 blockade that operates at the level of both tumor cells and leukocytes

Summary

Introduction

Major conceptual advances in cancer biology have been made over the past decade.[1,2,3] The understanding that immune responses are routinely generated against tumor-specific neoantigens resulting from cancer–associated mutations[4,5,6,7,8] and commonly suppressed by immunosuppressive tumor microenvironments (TME) has led to the development of effective immunotherapies aimed at provoking immune control against tumor progression.[9,10] Cancer immunotherapy has resulted in remarkable success in the treatment of a variety of hematological and solid metastatic malignancies such as melanoma, lung, bladder, kidney, Hodgkin’s lymphoma, B cell acute lymphocytic leukemia, hepatocellular carcinoma, Merkel-cell carcinoma and head and neck tumors.[11,12,13,14,15,16] To date, therapies that block inhibitory signaling molecules expressed by T lymphocytes (so called “immune checkpoints”) during the initial priming phase (in the draining lymph nodes) or the effector phases (in tumor beds) of adaptive anticancer immune responses have resulted in the greatest clinical benefit.[16,17] A paradigm of this success has been the use of monoclonal antibodies (mAb) targeting Programmed cell death 1 (PD-1) (expressed by activated/exhaustedT cells) or its ligand PD-L1 (commonly expressed by cancer cells or cells of the TME).[16,18] By releasing these molecular brakes, such mAbs reinstate the anticancer adaptive arm of the immune response. Major conceptual advances in cancer biology have been made over the past decade.[1,2,3] The understanding that immune responses are routinely generated against tumor-specific neoantigens resulting from cancer–associated mutations[4,5,6,7,8] and commonly suppressed by immunosuppressive tumor microenvironments (TME) has led to the development of effective immunotherapies aimed at provoking immune control against tumor progression.[9,10] Cancer immunotherapy has resulted in remarkable success in the treatment of a variety of hematological and solid metastatic malignancies such as melanoma, lung, bladder, kidney, Hodgkin’s lymphoma, B cell acute lymphocytic leukemia, hepatocellular carcinoma, Merkel-cell carcinoma and head and neck tumors.[11,12,13,14,15,16] To date, therapies that block inhibitory signaling molecules expressed by T lymphocytes (so called “immune checkpoints”) during the initial priming phase (in the draining lymph nodes) or the effector phases (in tumor beds) of adaptive anticancer immune responses have resulted in the greatest clinical benefit.[16,17] A paradigm of this success has been the use of monoclonal antibodies (mAb) targeting Programmed cell death 1 (PD-1) While PD-1 blockade represents the most effective first line therapy in BRAF wildtype melanoma and the best option in first-

Methods

Results

Conclusion