eIF5B drives integrated stress response-dependent translation of PD-L1 in lung cancer

Area of Science:

• Immunology
• Molecular Biology
• Oncology

Background:

• Tumor cells, including lung cancer, often express Programmed Death-Ligand 1 (PD-L1) to evade T cell-mediated anti-tumor immunity.
• Anti-PD-1/PD-L1 immunotherapies have shown significant clinical success, highlighting the importance of this immune checkpoint in cancer treatment.
• Understanding the regulatory mechanisms of PD-L1 expression is crucial for developing more effective cancer therapies.

Purpose of the Study:

• To identify novel regulators of PD-L1 expression in human lung cancer cells using CRISPR-based screening.
• To elucidate the molecular mechanisms by which heme biosynthesis impacts PD-L1 regulation and anti-tumor immunity.
• To investigate the role of the integrated stress response (ISR) and translation initiation factor eIF5B in PD-L1 expression.

Main Methods:

• CRISPR-based genetic screening in human lung cancer cells to identify PD-L1 regulators.
• Analysis of heme biosynthesis pathways and their effect on PD-L1 expression.
• Investigation of the integrated stress response (ISR) activation and its role in PD-L1 translation.
• Assessment of the requirement for the translation initiation factor eIF5B in ISR-dependent PD-L1 induction.
• Correlation of eIF5B overexpression with lung adenocarcinoma prognosis.

Main Results:

• Disruption of heme biosynthesis was found to potently induce PD-L1 expression in lung cancer cells.
• Impaired heme production activates the integrated stress response (ISR), which facilitates PD-L1 translation.
• ISR-mediated PD-L1 translation requires the translation initiation factor eIF5B.
• Overexpression of eIF5B, common in lung adenocarcinomas, is sufficient to induce PD-L1 expression.
• These mechanisms contribute to the suppression of anti-tumor immunity.

Conclusions:

• Heme biosynthesis critically regulates PD-L1 expression in lung cancer through the ISR.
• The translation initiation factor eIF5B plays a key role in ISR-dependent PD-L1 translation.
• eIF5B overexpression represents a mechanism for immune evasion in lung adenocarcinomas.
• Targeting heme biosynthesis, ISR, or eIF5B may offer novel therapeutic strategies for lung cancer.