Tumor Cell Programmed Death Ligand 1-Mediated T Cell Suppression Is Overcome by Coexpression of CD80

Abstract

Programmed death ligand 1 (PDL1, or B7-H1) is expressed constitutively or is induced by IFN-γ on the cell surface of most human cancer cells and acts as a “molecular shield” by protecting tumor cells from T cell-mediated destruction. Using seven cell lines representing four histologically distinct solid tumors (lung adenocarcinoma, mammary carcinoma, cutaneous melanoma, and uveal melanoma), we demonstrate that transfection of human tumor cells with the gene encoding the costimulatory molecule CD80 prevents PDL1-mediated immune suppression by tumor cells and restores T cell activation. Mechanistically, CD80 mediates its effects through its extracellular domain, which blocks the cell surface expression of PDL1 but does not prevent intracellular expression of PDL1 protein. These studies demonstrate a new role for CD80 in facilitating antitumor immunity and suggest new therapeutic avenues for preventing tumor cell PDL1-induced immune suppression.

PD-L1 Binds to B7-1 Only In Cis on the Same Cell Surface

“…Our data also support previous findings that coexpression of B7-1 on PD-L1 þ human tumor cells rendered PD-L1 undetectable by PD-1-Fc and by some human PD-L1 mAbs (29E.2A3, MIH1, and 27A2) although still detectable by 5H1 mAb (21,22). This result may be explained by B7-1 binding to PD-L1 sterically blocking the epitopes recognized by some antibodies (21).…”

“…Thus, a cis interaction modifies the threshold for a response to occur (30). The work by Haile and colleagues is compatible with the structural orientation of PD-L1 and B7-1, allowing binding in cis on the same cell or of soluble B7-1 to cell surface PD-L1 (20)(21)(22). Although some cell surface molecules bind the same receptor or ligand both in trans and in cis, the possibilities for PD-L1 are more restricted.…”

“…The evolutionary conservation and concentration-dependent blocking of PD-L1 interaction with B7-1 by PD-L1 antibodies also suggests the binding to be functionally relevant rather than a chance homology binding. Some studies have shown that B7-1 competes with PD-1 for binding to PD-L1 (20)(21)(22). We performed competition assays and showed that PD-1 and B7-1 competed for binding to PD-L1 and could block each other's binding.…”

Inflammation in uveal melanoma

“…49 The introduction of CD80 into tumour cells has a secondary effect, which is to block the ligand PDL1, which usually inhibits antitumour T-cell activity. 50 Another therapeutic approach, therefore, may be to block the interaction between ligand and receptor through anti-PDL1 or anti-PD-1 monoclonal antibodies. This is currently being investigated in other cancers in many trials.…”

Clinical deployment of antibodies for treatment of melanoma

“…The ligands for this receptor, (PD-L1 (B7-H1) and PD-L2 (B7-DC)), found on APC, macrophages, T cells and B cells are up-regulated at the time of T-cell activation. PD-L1 is also expressed by many tumors including melanoma (Haile et al, 2011). PD-1 can also interact with CD80, one of the ligands for CTLA-4, therefore expression of PD-1 can potentially reinforce the inhibitory signal from the CTLA-4 pathway (also known as coinhibition).…”