The programmed death-1 immune-suppressive pathway: barrier to antitumor immunity

Abstract

Programmed death ligand 1 (PD-L1, also known as B7 homolog 1 or CD274) is a major obstacle to antitumor immunity because it tolerizes/anergizes tumor-reactive T cells by binding to its receptor programmed death-1 (CD279), renders tumor cells resistant to CD8(+) T cell- and FasL-mediated lysis, and tolerizes T cells by reverse signaling through T cell-expressed CD80. PD-L1 is abundant 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 antitumor immunity has been demonstrated in multiple animal models and in recent clinical trials. This article reviews the mechanisms by which PD-L1 impairs antitumor immunity and discusses established and experimental strategies for maintaining T cell activation in the presence of PD-L1-expressing cells in the tumor microenvironment.

Figure 1. B7 and CD28 family members deliver costimulatory and coinhibitory signals to T cells

(A) T cells are activated when their TcR and CD28 receive antigen-specific signals delivered by peptide/MHC complexes (pMHC) and costimulatory signals such as CD80 (B7.1), respectively. Activated T cells up-regulate PD-1 and can then be suppressed by interaction with PD-L1⁺ cells. Signaling through PD-1 results in T cell apoptosis, exhaustion, and/or anergy, and involves phosphorylation of SHP2 which blocks the activation of ZAP70, AKT, PI3K, and PKCΘ which mediate the down-stream events that culminate in activation through the TcR. PD-1 signaling also activates Cbl-b and Smad3 which down-regulate cell surface expression of the TcR and cell proliferation, respectively, inhibits the anti-apoptotic gene Bcl-xL, and activates the pro-apoptotic gene Bim. PD-L1 also tolerizes peripheral T cells by reverse signaling through T cell-expressed CD80. Green and red lines indicate pathways that are activated and suppressed, respectively. (B) Crystal structure of the extracellular PD-L1:PD-1 complex (human PD-L1 and murine PD-1). PD-L1 (shown in red) consists of extracellular IgV and IgC domains. PD-1 (shown in blue) consists of a single extracellular IgV-like domain. (Structure is from (79)).

Figure 2. Multiple lymphoid and myeloid cell populations express PD-1 and are inhibited by PD-L1⁺ tumor cells or antigen presenting cells

(A) Binding of PD-L1⁺ cells to PD-1⁺ activated T cells can result in T cell dysfunction by causing T cell anergy, T cell exhaustion, T cell apoptosis, and by inducing the differentiation of T regulatory cells. PD-1 is also expressed by activated B cells, monocytes, NKT cells, macrophages, and dendritic cells and suppresses these cells. (B) PD-L1 also impairs anti-tumor immunity by protecting PD-L1⁺ tumor cells from CTL, presumably by inhibiting Fas or granzyme B-mediated cytolysis.

Figure 3. Soluble CD80 may facilitate anti-tumor immunity through three distinct mechanisms

Soluble CD80 may (i) prevent PD-L1⁺ cells (tumor cells, lymphoid cells, or other PD-L1⁺ cells) from anergizing PD-1⁺ activated T cells; (ii) prevent PD-L1⁺ cells from anergizing CD80⁺ T cells by reverse signaling through T cell-expressed CD80; and (iii) enhance T cell activation by costimulating tumor antigen-specific T cells through CD28.