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

Keisuke Kataoka1, Yuichi Shiraishi2, Yohei Takeda3

  • 1Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan.

Nature
|June 10, 2016
PubMed

Insights

Structural variations disrupting the 3' region of the PD-L1 gene are a novel mechanism for cancer immune escape. This PD-L1 3'-UTR disruption elevates PD-L1 expression, aiding tumor evasion and offering a potential biomarker.

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.

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