TYRO3 induces anti-PD-1/PD-L1 therapy resistance by limiting innate immunity and tumoral ferroptosis

Area of Science:

• Oncology
• Immunology
• Cancer Biology

Background:

• Immune checkpoint blockade (ICB) therapy, such as anti-programmed cell death protein 1/programmed death ligand 1 (anti-PD-1/PD-L1), shows promise in treating various cancers.
• However, primary and acquired resistance to ICB limits its clinical efficacy, necessitating the identification of predictive biomarkers and alternative therapeutic targets.

Purpose of the Study:

• To investigate the role of TYRO3 in mediating resistance to anti-PD-1/PD-L1 therapy.
• To explore TYRO3 as a potential predictive biomarker and therapeutic target for overcoming ICB resistance.

Main Methods:

• Utilized a syngeneic mouse model and patient data from anti-PD-1/PD-L1 therapy.
• Assessed the impact of TYRO3 expression on tumor ferroptosis and the tumor microenvironment, specifically the M1/M2 macrophage ratio.
• Investigated the therapeutic potential of TYRO3 inhibition in combination with anti-PD-1 therapy.

Main Results:

• Tumors with high TYRO3 expression demonstrated resistance to anti-PD-1/PD-L1 therapy in both mouse models and human patients.
• TYRO3 was found to inhibit anti-PD-1/PD-L1-induced tumor cell ferroptosis and promote a protumor microenvironment by decreasing the M1/M2 macrophage ratio.
• Inhibition of TYRO3 enhanced tumor ferroptosis and sensitized resistant tumors to anti-PD-1 therapy.

Conclusions:

• TYRO3 is a key mediator of resistance to anti-PD-1/PD-L1 therapy.
• TYRO3 functions by suppressing ferroptosis and promoting an immunosuppressive tumor microenvironment.
• Targeting TYRO3 represents a promising strategy to overcome ICB resistance and improve patient outcomes in cancer immunotherapy.