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

Area of Science:

• Immunology
• Cancer Biology
• Molecular Oncology

Background:

• Programmed cell death protein 1 (PD-1)/PD-1 ligand 1 (PD-L1) blockade shows promise in cancer treatment but faces resistance.
• Predictive biomarkers are crucial for optimizing anti-PD-L1 therapy efficacy.
• Interferon (IFN)-γ signaling pathway's role in regulating PD-L1 and MHC-I expression is under investigation.

Purpose of the Study:

• To investigate if loss-of-function mutations in interferon (IFN)-γ receptor 1 (IFNGR1) on tumor cells impact sensitivity to anti-PD-L1 therapy.
• To determine if IFNGR1 deactivation affects PD-L1 and major histocompatibility complex class I (MHC-I) expression on tumor cells.
• To evaluate IFNGR1 as a potential predictive biomarker for anti-PD-L1 cancer immunotherapy.

Main Methods:

• Utilized CRISPR/Cas9 to generate mouse TC-1 tumor cell lines with deactivated IFNGR1 (TC-1/dIfngr1 and TC-1/A9/dIfngr1).
• Assessed PD-L1 and MHC-I expression in vitro upon stimulation with IFN-α and IFN-β.
• Evaluated tumor sensitivity to anti-PD-L1 therapy in combination with DNA vaccination in vivo.

Main Results:

• IFNGR1 deactivation did not intrinsically reduce PD-L1 or MHC-I expression on tumor cells.
• IFN-α and IFN-β enhanced PD-L1 and MHC-I expression in IFNGR1-deactivated cells.
• Tumor cells with deactivated IFNGR1 maintained sensitivity to anti-PD-L1 therapy.

Conclusions:

• Impairment of IFN-γ signaling alone is insufficient to cause resistance to PD-L1 blockade.
• Loss of IFNGR1 function does not significantly alter PD-L1 or MHC-I expression in the context of IFN-α/β stimulation.
• IFNGR1 status should not be used as a sole predictive marker for anti-PD-1/PD-L1 cancer immunotherapy.