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.
Highlights
Programmed death-ligand 1 (PD-L1, referred to as B7 homolog 1 (B7-H1) or CD274) is constitutively expressed by cells of the myeloid lineage, including macrophages and dendritic cells [1,2,3]
When PD-L1 interacts with programmed death-1 (PD-1), the immunoreceptor tyrosine-based inhibitory motifs and immunoreceptor tyrosine-based switch motifs on the Abbreviations: APC, antigen-presenting cells; B7-H1, B7 homolog 1; Bim, Bcl-2-like protein 11; Hepatitis C virus (HCV), hepatitis C virus; HIF1α, hypoxia-inducible factor-1α; LCMV, lymphocytic choriomeningitis virus; MDC, myeloid dendritic cells; MDSC, myeloidderived suppressor cell; nonsmall cell lung cancer (NSCLC), non-small cell lung cancer; PD-L1, programmed death-ligand 1; soluble form of PD-L1 (sPD-L1), soluble PD-L1
Several studies have demonstrated that PD-L1 signaling during the priming phase limits CD8+ T cell responses, so PD-L1/PD-1 checkpoint blockade therapies likely work in part by enhancing CD8+ T cell responses by influencing events during the priming phase of an antitumor immune response
Summary
Programmed death-ligand 1 (PD-L1, referred to as B7-H1 or CD274) is constitutively expressed by cells of the myeloid lineage, including macrophages and dendritic cells [1,2,3]. 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. Some of the unpredictability of responses to PD-L1/PD-1 checkpoint blockade therapies may be due to the heterogeneity and dynamics of PD-L1 expression by tumor cells and immune cells, including dendritic cells and CD8+ T cells [34, 35].
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