PD-L1 deglycosylation promotes its nuclear translocation and accelerates DNA double-strand-break repair in cancer

Area of Science:

• Oncology
• Molecular Biology
• Cancer Research

Background:

• Radiotherapy resistance is a significant challenge in cancer treatment.
• The programmed death-ligand 1 (PD-L1) protein is known for its role in immune evasion.
• Its direct role in DNA repair and radioresistance is not well understood.

Purpose of the Study:

• To identify novel factors contributing to radioresistance in lung cancer.
• To elucidate the molecular mechanisms by which PD-L1 influences DNA repair and radiotherapy response.

Main Methods:

• Genome-scale CRISPR/Cas9 screening was employed to identify genes conferring resistance to ionizing radiation (IR).
• Depletion and overexpression of PD-L1 were used to assess its impact on DNA double-strand break (DSB) repair.
• Immunofluorescence, co-immunoprecipitation, and biochemical assays were utilized to study PD-L1 localization and interactions.

Main Results:

• Genome-scale CRISPR/Cas9 screening identified CD274 (encoding PD-L1) as a key mediator of lung cancer cell radioresistance.
• PD-L1 depletion delayed the repair of IR-induced DNA double-strand breaks (DSBs) and downregulated non-homologous end joining (NHEJ).
• Ionizing radiation induced PD-L1 translocation to the nucleus, where it interacts with Ku proteins to enhance DSB repair and promote radioresistance.

Conclusions:

• PD-L1 functions as a direct driver of non-homologous end joining (NHEJ)-mediated DSB repair, independent of its immune function.
• PD-L1 nuclear translocation and interaction with Ku are critical for accelerating DSB repair and conferring radioresistance.
• Targeting PD-L1's role in DNA repair may offer novel strategies to overcome radiotherapy resistance in cancer.