Abrogation of IFN-γ Signaling May not Worsen Sensitivity to PD-1/PD-L1 Blockade
| Autor: | Michal Smahel, Adrianna Piatakova, Ingrid Polakova, Julie Vackova |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
medicine.medical_treatment
Programmed Cell Death 1 Receptor Clone (cell biology) Major histocompatibility complex PD-1/PD-L1 Article B7-H1 Antigen Catalysis Inorganic Chemistry lcsh:Chemistry Interferon-gamma Mice Antineoplastic Agents Immunological Interferon PD-L1 MHC class I IFNGR1 Tumor Cells Cultured medicine Animals cancer Physical and Theoretical Chemistry Molecular Biology lcsh:QH301-705.5 Spectroscopy IFN-β Cell Line Transformed IFN-α Predictive marker biology Chemistry Organic Chemistry Neoplasms Experimental General Medicine Immunotherapy Computer Science Applications Blockade immune checkpoint therapy Mice Inbred C57BL lcsh:Biology (General) lcsh:QD1-999 biology.protein Cancer research Female medicine.drug |
| Zdroj: | International Journal of Molecular Sciences Volume 21 Issue 5 International Journal of Molecular Sciences, Vol 21, Iss 5, p 1806 (2020) |
| ISSN: | 1422-0067 |
| DOI: | 10.3390/ijms21051806 |
| Popis: | 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)-&gamma 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-&alpha and IFN-&beta enhanced PD-L1 and MHC-I expression on TC-1/dIfngr1 and TC-1/A9/dIfngr1 cells in vitro. Neutralization of the IFN-&alpha /IFN-&beta 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-&gamma 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. |
| Databáze: | OpenAIRE |
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