**1. Introduction**

Twenty-two years ago, Freeman et al. were the first to introduce programmed cell death-1 and its ligand (PD-1/PD-L1) as an immune checkpoint that later on was the immune inhibitor target in cancer therapy. Generally, checkpoints play a role as a brake to slow down the immune function, and it was proposed that inhibition of these checkpoints may stimulate T cells and eradicate malignant cells more effectively [1, 2].

In immune regulation, CD4+ regulatory T cell's role is well recognized; they suppress autoimmunity and allergic reactions, on the other side, they enable cancer growth by inhibiting immunity against neoplasms [3, 4].

Immune evasion by cancer cells is mediated through acquiring mechanisms of resistance and escape including creating an environment of immunosuppression

using immunosuppressive components such as molecules, cytokines of immune suppression type, and cells including CD4+ regulatory T cells to constrain active immunity against the tumor, thus endorsing tumor growth [4]. There is a suggestion of more malleability of the CD4+ regulatory T cell compartment expression with various aspects such as suppression function deactivation, inflammatory cytokines expression, and transcription reprogramming. Even though it is uncertain which element is responsible for CD4+ regulatory T cell malleability, there is probability that precise microenvironments have the inscription on CD4+ regulatory T cell destiny [5].

Numerous checkpoints of immune reaction have been established to bound the hyper-activation of immune cells involved in self-tolerance. One of the significant checkpoints is PD-1 and its ligands, PD-L1 and PD-L2 expressed mainly on the surface and in the body of lymphocytes, in antigen-presenting cells (APCs), and cancer cells and regulate responses toward antigens. Managing PD-1/PD-L actions facilitates the regulation of numerous immune-related disorders including infection, autoimmune disorders, and malignancies [6]. PD-L1 expression is related to microenvironment of T cells, cytokines produced by T cells of helper type, chemical mediators, interferons, and precise characters of gene expression. Continuous stimulation with an elevated level of PD-1 is frequently established in cancer inflammatory infiltrates mainly lymphocytes, as an expression of PD-L1 is utilized by neoplastic cells to escape immune damage. Blocking of these immune checkpoints is exploited to release the prospective of antagonistic therapy against cancer immune response as cancer treatment strategy [7].

Although there is a significant benefit in the outcome of patients attained with PD-L1/PD-1 blocking therapies, resistances are also commonly observed [8].

### **2. PD-1/PD-L1 immune checkpoint**

Programmed cell death-1(PD-1/CD279) has two identified ligands, PD-L1 and 2 (CD274 and CD273 respectively), each with distinct expression patterns and regulations, of which PD-L1 is expressed in numerous cancers [9]. PD-1 is a transmembrane glycoprotein type 1 of the immunoglobulin superfamily, out of its total 288 amino acids, a 20% amino acid shows distinctiveness to cytotoxic T lymphocyte antigen 4 (CTLA4) and it is encoded by the PDCD1 gene on chromosome 2. PD-1 is formed of an extracellular domain of IgV-like and a transmembrane section. Its tyrosine-based switch motif (ITSM) and inhibitory motif tyrosine base are forming the tail which is located intracellularly. It was considered a CD28 receptor family member of T cells accessory molecules. Although PD-1 has similarities to the CD28 family, it shows distinctive properties distinguishing it from members of such family [10, 11].

PD-1 expression on effector T cells is mediated due to stimulation of the T cell receptor (TCR) and it plays a role as a receptor of immune inhibition. It binds the PD-L1 B7 homologs (B7-H1) and PD-L2 (B7-DC), existing mainly on APCs, and can be prompted in other tissues by cytokines of inflammation [1, 6]. PD-1 has a tendency concerning moderate local activation of T cells in tissues of the periphery. PD-1 may have delayed actions in the T cell activation and decay. Generally, PD-1/ PD-L plays a significant role in sustaining T cell self-tolerance with the prevention of autoimmunity, and it reduces some anti-apoptotic molecules expression such as B-cell lymphoma-extra-large (BCL-XL) in addition to pro-inflammatory cytokines

*Immune Checkpoint Inhibitors Programmed Cell Death-1/Programmed Cell Death-Ligand1… DOI: http://dx.doi.org/10.5772/intechopen.108366*

secretion [12, 13]. The inhibitory function of PD-1/PD-L1 is mediated primarily on effector T cells but also it acts on regulatory T cells by affecting phosphatidyl-inositol 3 kinase (PI3K) to control T cell autoimmunity and tolerance. In general, tolerance is the failure of T cells that may be manifested as ignorance (failure of activation), or "anergic" status (responding cells are persistent in a refractory status), or deletion (apoptosis of T cell) [3, 14].

PDCDL1 gene on chromosome 9 is responsible for PD-L1 coding in humans, PD-L1 a transmembrane protein type 1 was documented as a member of the family B7 protein. The length of PD-L1 is 290 amino acids of 40 kDa protein. PD-L1 consists of extracellular domains (IgV-like & IgC-like), a transmembrane domain (hydrophobic), and a 30 amino acids cytoplasmic tail. The PD-L1 constitutive expression can be detected at low levels, on inactive lymphocytes, APCs, and in syncytiotrophoblasts, corneal, endothelial, keratinocytes, and Langerhans' islet cells of the pancreas as it plays a role in inflammatory response tissue homeostasis and giving a state of "immune privileged", as the introduction of external antigens is tolerated with no immune or inflammatory response. PD-L1 is prompted as an inhibitory signal in inflammation acting upon immune, epithelial, and endothelial cells [15, 16].

Toll-like receptors (TLRs) in APCs affect PD-L1 expression through MEK/ERK (extracellular signal-regulated kinase) kinases activation, in addition to receptors of Interferon-gamma (IFN-γ) 1 & 2 via Jak (Janus kinase)/STAT (Signal transducer and activator of transcription)-mediated activation that can also influence MEK/ERK and PI3K/AKT pathway [17]. PD-1/PDL-1 ligation leads to SHP-1/SHP-2 recruitment to the ITSM with dephosphorylation of kinases e.g. CD3ζ, PKCθ, and ZAP70 leading to a general inhibition of T cell spreading out which results from PI3K-Akt and Ras-MEK-ERK cascade inhibition mostly through direct inactivation effect of PD-1of Ras &dephosphorylation of phospholipase Cγ [15, 18]. Dephosphorylation of Casein kinase 2 (CK-2), which is an SHP-2 target, causes uncontrolled activation of PTEN (PI3K-Akt signaling antagonist) [16, 17]. It was also suggested that CD28 receptor co-stimulation, maybe the main dephosphorylation target by SHP2 phosphatase [19]. PD-1/PD-L1 engagement modifies variable T cell activities including T cell proliferation deactivation, cytokine induction, survival, and other functions [20], the reaction between PI3K signaling and BCL-XL is a significant point of control where PD-1 inhibition of P13K decreases BCL-XL and endorses apoptosis [21] (**Figure 1**).

The PD-1/PD-L1 interaction is critical for immune tolerance development, whether central or peripheral in primary or secondary lymphoid tissue respectively [22]. PD-1/PD-L1 knock-out in animal experiments causes autoimmunity with glomerulonephritis lupus-like arthritis and diabetes. While in humans, using antibodies against PD-1/PD-L1 leads to immune-related disorders such as endocrinopathy, colitis, and dermatoses [23–25]. A principal feature of T cell exhaustion, which is a marked weakening of effector T cell function, embraces the generation of several co-inhibitory pathways such as PD-1/PD-L1. Such impairment could be detected through apoptosis or inhibition of T cell development or production of regulatory T cells [26, 27]. The role of PD-1/PD-L1 is manifested in cases of T cell exhaustion, not only in chronic infection but also in cancer state [28, 29].

The greatest documented evidence of this inhibitory role in human immunity is derived from the usage of mediators to block the PD-1/PD-L1 pathway, an important target for immunotherapy in malignancy. Nevertheless, PD-1–PD-L1 interaction inhibition in patients suffering from malignancy causes anticancer immunity activation and autoimmune symptoms known as immune-associated opposing incidents [30].

**Figure 1.** *Activation pathways of PD-1/PD-L1 expression.*
