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Article

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

1
Department of Genetics and Microbiology, Faculty of Science, Charles University, BIOCEV, 252 50 Vestec, Czech Republic
2
Department of Cell Biology, Faculty of Science, Charles University, BIOCEV, 252 50 Vestec, Czech Republic
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2020, 21(5), 1806; https://doi.org/10.3390/ijms21051806
Received: 21 February 2020 / Revised: 4 March 2020 / Accepted: 4 March 2020 / Published: 6 March 2020
(This article belongs to the Special Issue Cancer Immunotherapy Using Checkpoint Inhibitors: Future Directions)
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. View Full-Text
Keywords: immune checkpoint therapy; cancer; PD-1/PD-L1; IFNGR1; IFN-α; IFN-β; MHC class I immune checkpoint therapy; cancer; PD-1/PD-L1; IFNGR1; IFN-α; IFN-β; MHC class I
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MDPI and ACS Style

Vackova, J.; Piatakova, A.; Polakova, I.; Smahel, M. Abrogation of IFN-γ Signaling May not Worsen Sensitivity to PD-1/PD-L1 Blockade. Int. J. Mol. Sci. 2020, 21, 1806. https://doi.org/10.3390/ijms21051806

AMA Style

Vackova J, Piatakova A, Polakova I, Smahel M. Abrogation of IFN-γ Signaling May not Worsen Sensitivity to PD-1/PD-L1 Blockade. International Journal of Molecular Sciences. 2020; 21(5):1806. https://doi.org/10.3390/ijms21051806

Chicago/Turabian Style

Vackova, Julie, Adrianna Piatakova, Ingrid Polakova, and Michal Smahel. 2020. "Abrogation of IFN-γ Signaling May not Worsen Sensitivity to PD-1/PD-L1 Blockade" International Journal of Molecular Sciences 21, no. 5: 1806. https://doi.org/10.3390/ijms21051806

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