Aberrant PD-L1 expression through 3'-UTR disruption in multiple cancers.

Area of Science:

• Oncology
• Immunology
• Genetics

Background:

• Antibodies targeting programmed cell death 1 (PD-1) and its ligand (PD-L1) have shown success in treating advanced cancers.
• PD-1/PD-L1-mediated immune escape is crucial in cancer development, but its genetic underpinnings are not fully understood.
• Known mechanisms include gene amplification and translocation-driven ectopic promoter use for PD-L1 elevation.

Purpose of the Study:

• To investigate novel genetic mechanisms driving PD-L1 overexpression and cancer immune escape.
• To identify structural variations (SVs) affecting the PD-L1 gene and their functional consequences.
• To explore the potential of PD-L1 3 -untranslated region (UTR) disruption as a biomarker for immune evasion.

Main Methods:

• Analysis of structural variations (SVs) in the 3 region of the PD-L1 gene across various human cancers.
• Assessment of PD-L1 transcript levels and stability following SVs.
• In vivo mouse models to evaluate the impact of PD-L1 3 -UTR disruption on tumor immune evasion and response to PD-1/PD-L1 blockade.

Main Results:

• Common SVs disrupting the PD-L1 3 region were identified in multiple cancer types, including adult T-cell leukaemia/lymphoma (27%), diffuse large B-cell lymphoma (8%), and stomach adenocarcinoma (2%).
• These SVs lead to elevated aberrant PD-L1 transcripts stabilized by 3 -UTR truncation.
• Disruption of the mouse Pd-l1 3 -UTR promoted tumor immune evasion, which was sensitive to Pd-1/Pd-l1 blockade.

Conclusions:

• Structural variations truncating the PD-L1 3 -UTR represent a novel mechanism for immune escape in cancer.
• This genetic alteration leads to increased PD-L1 expression and facilitates tumor evasion of anti-tumor immunity.
• PD-L1 3 -UTR disruption can serve as a genetic marker to identify cancers employing this immune evasion strategy.