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Identification and characterization of an alternative cancer-derived PD-L1 splice variant.

Cancer immunology, immunotherapy : CII (2018-12-20)
Nadia B Hassounah, Venkat S Malladi, Yi Huang, Samuel S Freeman, Ellen M Beauchamp, Shohei Koyama, Nicholas Souders, Sunil Martin, Glenn Dranoff, Kwok-Kin Wong, Chandra S Pedamallu, Peter S Hammerman, Esra A Akbay
ABSTRACT

Therapeutic blockade of the PD-1/PD-L1 axis is recognized as an effective treatment for numerous cancer types. However, only a subset of patients respond to this treatment, warranting a greater understanding of the biological mechanisms driving immune evasion via PD-1/PD-L1 signaling and other T-cell suppressive pathways. We previously identified a head and neck squamous cell carcinoma with human papillomavirus integration in the PD-L1 locus upstream of the transmembrane domain-encoding region, suggesting expression of a truncated form of PD-L1 (Parfenov et al., Proc Natl Acad Sci USA 111(43):15544-15549, 2014). In this study, we extended this observation by performing a computational analysis of 33 other cancer types as well as human cancer cell lines, and identified additional PD-L1 isoforms with an exon 4 enrichment expressed in 20 cancers and human cancer cell lines. We demonstrate that cancer cell lines with high expression levels of exon 4-enriched PD-L1 generate a secreted form of PD-L1. Further biochemical studies of exon 4-enriched PD-L1 demonstrated that this form is secreted and maintains the capacity to bind PD-1 as well as to serve as a negative regulator on T cell function, as measured by inhibition of IL-2 and IFNg secretion. Overall, we have demonstrated that truncated forms of PD-L1 exist in numerous cancer types, and have validated that truncated PD-L1 can be secreted and negatively regulate T cell function.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Trichloroacetic acid solution, 6.1 N
Sigma-Aldrich
Monoclonal Anti-Vinculin antibody produced in mouse, clone hVIN-1, ascites fluid
Sigma-Aldrich
Human PDCD1 / Programmed Cell Death Protein 1 ELISA Kit