Functional Expression of Programmed Death-Ligand 1 (B7-H1) by Immune Cells and Tumor Cells

Abstract

The programmed death-1 (PD-1) and its ligand PD-L1 (B7-H1) signaling pathway has been the focus of much enthusiasm in the fields of tumor immunology and oncology with recent FDA approval of the anti-PD-1 antibodies pembrolizumab and nivolumab and the anti-PD-L1 antibodies durvalumab, atezolimuab, and avelumab. These therapies, referred to here as PD-L1/PD-1 checkpoint blockade therapies, are designed to block the interaction between PD-L1, expressed by tumor cells, and PD-1, expressed by tumor-infiltrating CD8⁺ T cells, leading to enhanced antitumor CD8⁺ T cell responses and tumor regression. The influence of PD-L1 expressed by tumor cells on antitumor CD8⁺ T cell responses is well characterized, but the impact of PD-L1 expressed by immune cells has not been well defined for antitumor CD8⁺ T cell responses. Although PD-L1 expression by tumor cells has been used as a biomarker in selection of patients for PD-L1/PD-1 checkpoint blockade therapies, patients whose tumor cells lack PD-L1 expression often respond positively to PD-L1/PD-1 checkpoint blockade therapies. This suggests that PD-L1 expressed by non-malignant cells may also contribute to antitumor immunity. Here, we review the functions of PD-L1 expressed by immune cells in the context of CD8⁺ T cell priming, contraction, and differentiation into memory populations, as well as the role of PD-L1 expressed by tumor cells in regulating antitumor CD8⁺ T cell responses.

Keywords: B7-H1 (programmed death-ligand 1); CTL; T cells; immunotherapy; programmed death-1:programmed death-ligand 1 blockade; tumor.

Figure 1

The programmed death ligand-1 (PD-L1) (B7-H1) pathway in regulation of T cell responses to tumors. Once naïve T cells encounter cognate antigen presented by antigen-presenting cells (APC), they are primed and express PD-1 and CD80, two receptors of PD-L1. PD-1 once engaged by its ligand recruits the phosphatase SHP-2 to inhibit AKT activation by preventing CD28-mediated activation of PI3K. Along with CD80, PD-1 suppresses T cell expansion, and limits differentiation to memory cells by upregulation of Bim. Following expansion, T cells undergo contraction in which PD-L1 expressed by activated T cells provides pro-survival signals to T cells by upregulating Bcl-xl and inhibiting p38 MAPK activation. After arriving at the tumor site, PD-L1 expressed by tumor cells or tumor-associated macrophages or MDSCs suppresses the function of tumor-reactive T cells by inducing either apoptosis or exhaustion. MDSC, myeloid-derived suppressor cells; Bim, Bcl-2-like protein 11.