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

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

Research output: Contribution to journalArticle

7 Scopus citations

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 USA111(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.

Original languageEnglish (US)
Pages (from-to)407-420
Number of pages14
JournalCancer Immunology, Immunotherapy
Volume68
Issue number3
DOIs
StatePublished - Mar 13 2019

Keywords

  • Cancer immunology
  • HPV
  • PD-L1
  • Secreted PD-L1

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Oncology
  • Cancer Research

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  • Cite this

    Hassounah, N. B., Malladi, V. S., Huang, Y., Freeman, S. S., Beauchamp, E. M., Koyama, S., Souders, N., Martin, S., Dranoff, G., Wong, K. K., Pedamallu, C. S., Hammerman, P. S., & Akbay, E. A. (2019). Identification and characterization of an alternative cancer-derived PD-L1 splice variant. Cancer Immunology, Immunotherapy, 68(3), 407-420. https://doi.org/10.1007/s00262-018-2284-z