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Review
. 2020 Oct 21:11:568931.
doi: 10.3389/fimmu.2020.568931. eCollection 2020.

The Extrinsic and Intrinsic Roles of PD-L1 and Its Receptor PD-1: Implications for Immunotherapy Treatment

Katie Hudson  1 , Neil Cross  1 , Nicola Jordan-Mahy  1 , Rebecca Leyland  1
Affiliations
Review

The Extrinsic and Intrinsic Roles of PD-L1 and Its Receptor PD-1: Implications for Immunotherapy Treatment

Katie Hudson et al. Front Immunol. .

Abstract

Programmed death-ligand 1 (PD-L1) is an immune checkpoint inhibitor that binds to its receptor PD-1 expressed by T cells and other immune cells to regulate immune responses; ultimately preventing exacerbated activation and autoimmunity. Many tumors exploit this mechanism by overexpressing PD-L1 which often correlates with poor prognosis. Some tumors have also recently been shown to express PD-1. On tumors, PD-L1 binding to PD-1 on immune cells promotes immune evasion and tumor progression, primarily by inhibition of cytotoxic T lymphocyte effector function. PD-1/PD-L1-targeted therapy has revolutionized the cancer therapy landscape and has become the first-line treatment for some cancers, due to their ability to promote durable anti-tumor immune responses in select patients with advanced cancers. Despite this clinical success, some patients have shown to be unresponsive, hyperprogressive or develop resistance to PD-1/PD-L1-targeted therapy. The exact mechanisms for this are still unclear. This review will discuss the current status of PD-1/PD-L1-targeted therapy, oncogenic expression of PD-L1, the new and emerging tumor-intrinisic roles of PD-L1 and its receptor PD-1 and how they may contribute to tumor progression and immunotherapy responses as shown in different oncology models.

Keywords: PD-1; PD-1/PD-L1-targeted therapy; biomarkers; immunotherapy; novel therapeutic strategies; oncology models; programmed death-ligand 1; tumor-intrinsic role.

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Figures

Figure 1
Figure 1
The process of cancer immuno-editing: elimination, equilibrium and escape. Normal healthy cells transform into tumor cells through acquiring mutations that allows for uncontrolled growth of the cell. In the elimination phase, immune cells can recognize and eliminate tumor cells by inducing apoptosis via granule and/or receptor-mediated mechanisms. Some tumor cells avoid immune destruction and enter dynamic equilibrium with immune cells whereby the immune system elicits a potent enough response to contain the tumor cells but not enough to eradicate them. During this phase tumor cells develop increased genetic instability and undergo immune selection, whereby the immune cells eliminate those tumor cells susceptible to immune-mediated killing, whilst selecting those tumor cells with mechanisms to evade the immune system. These selected tumor cells can now proliferate freely and expand leading to immune escape. PD-L1 expression is one of the many mechanisms employed by tumors to facilitate immune evasion and tumor development. Tumor-intrinsic mutations can induce PD-L1 expression and influence tumor cell-immune cell interactions within the tumor microenvironment to favor tumor growth (as discussed later in this review). Interferon gamma (IFN-γ), tumor necrosis factor alpha (TNF-α), tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), interleukin 10 (IL-10), interleukin 6 (IL-6), transforming growth factor beta (TGF-β), hypoxic inducible factor 1/2 alpha (HIF-1/2α), vascular endothelial growth factor (VEGF), matrix metalloproteinases (MMPs).
Figure 2
Figure 2
The extrinsic function of the PD-1/PD-L1 signaling axis in cancer. T cells play an important role in modulating immune responses against tumor cells, but tumors can exhibit immune inhibitory mechanisms like overexpressing PD-L1 to avoid T cell-mediated killing. (A) When PD-L1 binds to PD-1 expressed on the surface of T cells, T cells become inactivated through the recruitment of SHP1/2 which subsequently inhibits TCR and CD28 co-stimulatory signaling by preventing the phosphorylation of ZAP70 and PI3K, leading to T cell anergy or apoptosis and ultimately immune evasion. (B) Monoclonal antibodies targeting the PD-1/PD-L1 signaling axis have been developed to restore immune-mediated eradication of the tumor. PD-1/PD-L1 blockade allows co-stimulatory signal transduction from the TCR and CD28 on T cells upon interaction with APCs or tumor cells. TCR binding to the tumor-associated antigen (TAA) in the MHC complex leads to the phosphorylation of ZAP70, which then phosphorylates P38 and LAT resulting in activation of calcium-dependent and MAPK pathways. Simultaneously, CD80 binding to CD28 phosphorylates PI3K which activates PIP3 leading to AKT-mTOR pathway activation. These signaling pathways promote T cell activation, cytokine production and pro-survival factor expression stimulating anti-tumor immunity.
Figure 3
Figure 3
The mechanisms of PD-L1 activation and inactivation in cancer. The diagram highlights the many mechanisms behind PD-L1 regulation in tumor cells and whether the proposed mechanisms have been shown to upregulate (+) or downregulate (−) the expression of PD-L1. PD-L1 expression is regulated at the transcriptional, post transcriptional, translational, and post translational level in tumor cells. Many mechanisms have been shown to modulate PD-L1 expression including genetic aberrations, epigenetic modifications, oncogenic and tumor suppressor signals and extrinsic factors.
Figure 4
Figure 4
The proposed mechanism of action of PD-L1 in tumor cell signaling. In select cancer types, there is an emerging role of PD-L1 to send pro-survival signals in tumor cells. There is little known about the mechanisms behind PD-L1 signal transduction in tumor cells and more research is required to fully elucidate the potential mechanisms responsible. However, PD-L1 signaling in some tumor cells has been shown to promote cancer initiation, epithelial to mesenchymal transition (EMT), invasion and metastasis, regulate glucose metabolism, and contribute to drug resistance. TAA, Tumor-associated antigen.
Figure 5
Figure 5
The new and emerging role of PD-1 signaling in cancer. (A) Intrinsic PD-1 signaling has been shown to promote tumorigenesis in melanoma, liver, and bladder cancer cells. Anti-PD-1 therapy abrogates this effect inhibiting tumor growth. (B) Intrinsic PD-1 signaling in NSCLC and colorectal cancer cells has been shown to inhibit tumorigenesis. Anti-PD-1 therapy preventing PD-1 signaling promotes tumor progression in NSCLC and colorectal cancer cells.
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