Samuel Haile, Ph.D.

 

Biological Sciences 2013

Area of Doctoral Study: Biological Sciences
Undergraduate Institute: Jackson State University

Research Advisor: Suzanne Ostrand Rosenberg, Ph.D.

Current Position: Scientist, Cell Design Labs

Description of Research

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 genetically 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 mAbs that detect distinct PDL1 epitopes, we have observed that over-expression of CD80 in vaccine cells blocks constitutive and IFNγ -induced expression of cell surface PDL1. CD80 and PDL1 expression display an inverse relationship with cells expressing high levels of CD80 having the least PDL1 and vice-versa. This CD80: PDL1 relationship has been observed in vaccines prepared from human lung, uveal melanoma, cutaneous melanoma, and breast cancer cells. Studies demonstrating intracellular expression of PDL1 in CD80+ tumor cells suggest that CD80 regulates PDL1 at the protein level. This hypothesis is supported by the findings that CD80 mutants lacking their cytoplasmic domain or with an irrelevant HLA-DRα, non-signaling cytoplasmic tail retain the ability to down-regulate PDL1, indicating that CD80 does not modulate PDL1 transcription via intracellular signaling. These results demonstrate that in addition to serving as a costimulatory molecule, CD80 facilitates T cell activation by blocking co-inhibitory signals and preventing T cell apoptosis.”