The Role of Programmed Death Ligand -1 (Pdl-1) in Lung Cancer

Lung cancer is the leading cause of cancer death worldwide. In 2018, it represented 11.6% of total cancer cases and 18.4% of total cancer deaths, making it the most frequent cancer and cause of cancer death in men and women combined .In Egypt, Lung cancer represents the most lethal malignancy and the fourth most common cancer in men.It is relatively more common in men. This gender difference in incidence is mainly due to differences in tobacco smoking rates, as smoking represents the major risk factor of this disease.

Programmed cell death 1 (PD-1) (Entrez Gene: 29126) and its ligand, programmed cell death ligand-1 (PDL-1) are new members of the CD28/B7 stimulatory superfamily. They mediate a negative signal, which inhibits functioning and proliferation of T and B cells, and reduce interleukin-2(IL-2), IL-10, and interferon-γ secretions.This inhibitory pathway is closely related to tumor progression, it provides an immune escape for tumor cells through cytotoxic T-cell inactivation. It plays an important role in the microenvironment of the tumor progress.Expression of this gene in tumor cells is prognostic in many types of human malignancies.Interaction of this ligand with its receptor inhibits T-cell activation and cytokine production. During infection or inflammation of normal tissue, this interaction is important for preventing autoimmunity by maintaining homeostasis of the immune response with local immune tolerance to tumors.

The biologically active form of Vit D, namely calcitriol or 1,25-dihydroxy Vitamin D (1,25(OH)2D ), is generated when 25(OH)D is hydroxylated in the kidneys by the cytochrome 1-α- hydroxylase enzyme (CYP27B1) (RXR) Yet, Vit. D has controversial effects; it has been shown to induce apoptosis of cancer cells and likely to play a promising role in cancer therapy.Numerous studies have proposed a strong relationship between low serum Vit. D levels and increased risk of cancer, especially by the strongest evidence in breast and colorectal cancer.

The biological actions as anti-cancer effects of calcitriol are mostly exerted through genomic actions mediated by the VDR and its existence in the numerous tumor tissues is suggestive of its role in tumor genesis.The VDR is a member of the nuclear receptor/steroid hormone receptor superfamily. These receptors function as ligand-activated, transcriptional regulatory proteins.VDR/RXR complex translocates into the nucleus and induces the transcription of phosphoinositide phospholipase C-γ1 (PLC-γ1) through interaction with Vit.D responsive element (VDRE) on specific genes.

There is an up-regulation of VDR upon exposure to Vit.D. The anti-proliferative and pro differentiating effects of Vit.D are mostly mediated through the nuclear VDR.In many types of cancers, decreased VDR expression has been found in advanced neoplasms.It was demonstrated a differential expression of VDR (nuclear/cytoplasm) in progression of normal to invasive squamous cell carcinoma.