Programmed Death Ligand-1 expression on the cell surface is regulated by costimulatory molecule CD80 expressed by cancer vaccines (101.4)

Abstract

Abstract Programmed Death Ligand 1 (PDL1) is a major obstacle in the development of cancer immunotherapies. PDL1 is constitutively expressed or induced by IFNγ on many tumor cells, resulting in the prevention of T cell activation or the apoptotic cell death of activated T cells. Cell-based vaccines previously developed in our lab were made by modifying tumor cells to express Major Histocompatibility Complex Class II (MHCII) and costimulatory B7-1 (CD80) molecules. These cell-based vaccines do not express PDL1, even after IFNγ stimulation. As determined by flow cytometry using three anti-PDL1 monoclonal antibodies that detect distinct PDL1 epitopes, and human lung, uveal and cutaneous melanoma, and breast cancer cells, the over-expression of CD80 blocks constitutive and IFNγ-induced cell surface expression of PDL1. Quantitative analysis of CD80 and PDL1 expression indicates an inverse relationship between PDL1 and CD80. CD80+ tumor cells contain intracellular PDL1, as assessed by flow cytometry, suggesting that CD80 regulates PDL1 at the protein level. Tumor cells transfected with CD80 constructs lacking a cytoplasmic domain or with an irrelevant non-signaling cytoplasmic domain, retain the ability to block PDL1 expression at the cell surface indicating that CD80 does not modulate PDL1 transcription. These results suggest that in addition to serving as a costimulatory molecule, CD80 facilitates T cell activation by blocking coinhibitory signals and preventing T cell apoptosis.