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PD-1/PD-L1 Signaling Pathway

Figure 1. The PD-1/PD-L1 signaling pathway

Introduction

Programmed cell death protein 1, also known as PD-1 and CD279, is a cell surface receptor that plays an important role in down-regulating the immune system and promoting self-tolerance by suppressing T cell inflammatory activity. In humans, it is encoded by the PDCD1 gene. PD-1 is a member of the immunoglobulin superfamily and is expressed on T-cells and pro-B cells. As a receptor, PD-1 has two ligands, PD-L1 (B7-H1) and PD-L2 (B7-DC). When PD-1 binds its ligands, it will induce a dual mechanism of promoting apoptosis (programmed cell death) in antigen-specific T-cells in lymph nodes while simultaneously reducing apoptosis in regulatory T-cells (anti-inflammatory, suppressive T-cells).

Depending upon the previous study, we find PD-L1 is responsible for tumor immune modulation. Because the binding affinity of PD-1 with PD-L1 is 3 times greater than the affinity between PD-1 for PD-L2 and PD-L1 expressions in tumor cells and hematopoietic cells are determined by the stimulation of pro-inflammatory cytokines such as IFN-γ and TNF-α. While PD-L1 is expressed in a wide range of hematopoietic and non-hematopoietic cells, PD-L2 has restricted expression on macrophages, dendritic cells (DCs) and mast cells in the secretion of IL-4 and IFN–γ. It has been recently reported that PD-L2 interacts with repulsive guidance molecule B (RGMB) of macrophage (M8) proteins. Although, there are several reports on PD-L2, little information is available about its role in cancer immunosuppression.

Mechanism of PD-1and PD-L1/L2 mediated immune resistance

The PD-1/PD-L signaling pathway regulates both the induction and the maintenance of peripheral tolerance. PD-L achieves this function of inducing T cell tolerance by expression in tolerogenic dendritic cells. Besides, PD-L1 is constitutively expressed on APCs and dendritic cells and is further upregulated by proinflammatory cytokines. When T cells are activated, PD-L1 is upregulated. After initial T cell activation, PD-1/PD-L interactions can limit self-reactive T cell proliferation and cytokine production.

In the tumor microenvironment, PD-1 and its ligand PD-L1 perform a vital role in tumor progression and survival by escaping tumor neutralizing immune surveillance. It has been found that PD-1 is expressed on a variety of immune cells, tumor-infiltrating lymphocytes (TILs) and tumor cells, and the engagement of PD-L1 with PD-1 of T cell creates T cell dysfunction, exhaustion, neutralization, and interleukin-10 (IL-10) production in a tumor mass. Therefore, the function of a tumor over-exerting PD-L1 is to protect itself from cytotoxic T cell (CD8+) mediated cell killing. Due to exhaustion of CD8+ T cells, tumor cells become very aggressive and secrete several pro-inflammatory cytokines. These cytokines further upregulate PD-L1. Another subtype of T cells, such as regulatory T cells (Treg, CD4+ Foxp3+) creates a highly immunosuppressive tumor environment through maintaining the expression of PD-1 on its surface. It has been observed that in the presence of CD3 and TGF-β, the PD-1 receptor of the regulatory T cells(Treg cells) increases the de novo transformation of naive CD4+ T-cells to Treg cells, thus attenuating immune responses. This conversion increases Treg expression and immune suppressive function of CD4+ T cell through inhibition of mammalian target of rapamycin (mTOR) -Akt signaling cascade. Thus, the presence of PD-1 expression not only suppresses effector T-cell function but also enhances the conversion of the immunosuppressive Treg cell population.

Even though PD-1 has widely been studied in T-cells, its functions in B-cells have also become apparent for tumor immunosuppression. It has been noted that PD-1 expression is highly regulated during B cell differentiation, but PD-1 levels are insignificant in pro-B cells and increase with B cell differentiation. Additionally, maturation of B-cells can significantly be enhanced by PD-1 activated toll-like receptor 9 (TLR9) agonists. Thus, inhibition of PD-1 function on B cells has been shown to enhance antigen-specific antibody responses, indicating that PD-1 plays a role in suppressing B cell mediated T-cell activation.

Cancer immunotherapy

In cancer immunotherapy, antigen-presenting cells (APCs) bind to antigen (Ag) that are released from tumor cells and T cells to activate T-cell receptor (TCR) and MHC binding. PD-L1 of tumor stroma interacts with PD-1 of T cells to suppress the T-cell mediated tumor cytotoxicity; if anti-PD-1 and PD-L1 drugs are used, T cell-mediated tumour cytotoxicity can be increased by blocking PD-1 or PD-L1, and eventually killing the tumour cells.

Unlike early activated CTLA-4, which modulates systemic T lymphocyte immunity, the PD-1 checkpoint only regulates the activity of cytotoxic T lymphocyte migration into tumors. The expression of PD-L1 ligand is selective and is not over-expressed in normal inflammatory tissues. This makes it possible to block the biological effects of the PD-1 pathway drug, which is much less toxic than anti-CTLA-4.The results of a small first trial of the anti-PD-1 drug nivolumab were very successful. In the following clinical trials, a significant portion of obstinate melanoma, renal and lung cancers also observed tumor regression. Lung cancer that was previously regarded as non-immunogenic (cannot cause immune rejection) proved to be resistant to PD-1. This discovery immediately switched the vision of PD-1 applications, and researchers conducted multiple clinical trials of anti-PD-1 and anti-PD-L1 drugs in various cancer types. Since the initial approval of anti-PD-1 monoclonal antibodies for advanced melanoma in early 2014, there have been six different drugs that have entered clinical practice for various indications. These indications include non-small cell lung cancer, Hodgkin's lymphoma and skin Merkel cell carcinoma, kidney, bladder, head and neck cancers, and tumors with high mutation burden genetic markers called microsatellite instability. These demonstrate that anti-PD-1 and anti-PD-L1 drugs may take as broad-spectrum anti-tumor drugs in tumors that express PD-L1.

Reference:

  1. Francisco L M., et al. The PD-1 pathway in tolerance and autoimmunity. Immunological Reviews.2010, 236: 219–42.
  2. Arlene H S., et al. The function of programmed cell death 1 and its ligands in regulating autoimmunity and infection. NATURE IMMUNOLOGY. 2007, 8: 239-245.
  3. Hashem O A., et al. PD-1 and PD-L1 Checkpoint Signaling Inhibition for Cancer Immunotherapy: Mechanism, Combinations, and Clinical Outcome. Frontiers in Pharmacology. 2017, 8: 1-15.

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