No abstract

Programmed Death Ligand 1 (PD-L1, also known as B7 homolog 1 (B7-H1) or CD274) is a major obstacle to anti-tumor immunity because it (i) tolerizes/anergizes tumor-reactive T cells by binding to its receptor PD-1 (CD279); (ii) renders tumor cells resistant to CD8+ T cell and FasL-mediated lysis; and (iii) tolerizes T cells by reverse signalling through T cell-expressed CD80. PD-L1 is abundantly present in the tumor microenvironment where it is expressed by many malignant cells as well as by immune cells and vascular endothelial cells. The critical role of PD-L1 in obstructing anti-tumor immunity has been demonstrated in multiple animal models and in recent clinical trials. This article reviews the mechanisms by which PD-L1 impairs anti-tumor immunity and discusses established and experimental strategies for maintaining T cell activation in the presence of PD-L1-expressing cells in the tumor microenvironment.

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.

Many tumor cells escape anti-tumor immunity through their expression of Programmed Death Ligand 1 (PDL1 or B7-H1), which interacts with T cell-expressed PD1 and results in T cell apoptosis. We previously reported that transfection of human tumor cells with a membrane-bound form of the human costimulatory molecule CD80 prevented PD1 binding and restored T cell activation. We now report that a membrane-bound form of murine CD80 similarly reduces PDL1-PD1-mediated suppression by mouse tumor cells, and that a soluble protein consisting of the extracellular domains of human or mouse CD80 fused to the Fc domain of IgG1 (CD80-Fc) overcomes PDL1-mediated suppression by human and mouse tumor cells, respectively. T cell activation experiments with human and mouse tumor cells indicate that CD80-Fc facilitates T cell activation by binding to PDL1 to inhibit PDL1-PD1 interactions and by costimulating through CD28. CD80-Fc is more effective in preventing PD1-PDL1-mediated suppression and restoring T cell activation compared to treatment with mAb to either PD1 or PDL1. These studies identify CD80-Fc as an alternative and potentially more efficacious therapeutic agent for overcoming PDL1-induced immune suppression and facilitating tumor-specific immunity.

Tumor cells employ various methods of immune suppression to overcome antitumor immunity. One such method is that of programmed death ligand-1 (PD-L1 or B7-H1), which upon binding its receptor programmed death-1 (PD-1) on T cells triggers apoptotic death of the activated T cells. Over-expression of the costimulatory molecule CD80 on PD-L1+ tumor cells, or inclusion of a soluble form of CD80 (CD80-Fc) maintains the activation of PD-1+ activated T cells. Using T cells from CD28-deficient mice and antibodies to block CD28 on human T cells, we now report that a soluble form of CD80 mediates this effect by simultaneously neutralizing the PD-1/PD-L1-mediated immune suppression and by providing CD80-CD28 costimulation. In summary, PD-L1 is a potent mediator of immune suppression that inhibits antitumor immunity in many cancer patients. In this study, we show that a soluble form of the costimulatory molecule CD80 increases the production of IFNγ by PD-1+ activated T cell more effectively than antibodies to PD-1 or PD-L1. Therefore, soluble CD80 may be a more effective therapeutic than these checkpoint antibodies for facilitating the development and maintenance of antitumor immunity because it has the dual functions of preventing PD-L1-mediated immune suppression and simultaneously delivering the second signal for T-cell activation.