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Abrogation of IFN-γ Signaling May not Worsen Sensitivity to PD-1/PD-L1 Blockade

J. Vackova, A. Piatakova, I. Polakova, M. Smahel,

. 2020 ; 21 (5) : . [pub] 20200306

Language English Country Switzerland

Document type Journal Article

Grant support
988218 Grantová Agentura, Univerzita Karlova
LQ1604 Ministerstvo Školství, Mládeže a Tělovýchovy
LM2018126 Ministerstvo Školství, Mládeže a Tělovýchovy
CZ.1.05/1.1.00/02.0109 European Regional Development Fund
CZ.1.05/2.1.00/19.0400 European Regional Development Fund
CZ.02.1.01/0.0/0.0/16_019/0000785 European Regional Development Fund
CZ.1.05/2.1.00/19.0395 European Regional Development Fund

Programmed cell death protein 1 (PD-1)/PD-1 ligand 1 (PD-L1) blockade is a promising therapy for various cancer types, but most patients are still resistant. Therefore, a larger number of predictive biomarkers is necessary. In this study, we assessed whether a loss-of-function mutation of the interferon (IFN)-γ receptor 1 (IFNGR1) in tumor cells can interfere with anti-PD-L1 therapy. For this purpose, we used the mouse oncogenic TC-1 cell line expressing PD-L1 and major histocompatibility complex class I (MHC-I) molecules and its TC-1/A9 clone with reversibly downregulated PD-L1 and MHC-I expression. Using the CRISPR/Cas9 system, we generated cells with deactivated IFNGR1 (TC-1/dIfngr1 and TC-1/A9/dIfngr1). In tumors, IFNGR1 deactivation did not lead to PD-L1 or MHC-I reduction on tumor cells. From potential inducers, mainly IFN-α and IFN-β enhanced PD-L1 and MHC-I expression on TC-1/dIfngr1 and TC-1/A9/dIfngr1 cells in vitro. Neutralization of the IFN-α/IFN-β receptor confirmed the effect of these cytokines in vivo. Combined immunotherapy with PD-L1 blockade and DNA vaccination showed that IFNGR1 deactivation did not reduce tumor sensitivity to anti-PD-L1. Thus, the impairment of IFN-γ signaling may not be sufficient for PD-L1 and MHC-I reduction on tumor cells and resistance to PD-L1 blockade, and thus should not be used as a single predictive marker for anti-PD-1/PD-L1 cancer therapy.

References provided by Crossref.org

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