Human PD1/PDL1 programmed cell death protein 1/Programmed cell death 1 ligand 1

Programmed cell death protein 1 (PDCD1) is an immune-inhibitory receptor expressed in activated T cells; it is involved in the regulation of T-cell functions, including those of effector CD8+ T cells. In addition, this protein can also promote the differentiation of CD4+ T cells into T regulatory cells. PDCD1 is expressed in many types of tumors including melanomas, and has demonstrated to play a role in anti-tumor immunity. Moreover, this protein has been shown to be involved in safeguarding against autoimmunity, however, it can also contribute to the inhibition of effective anti-tumor and anti-microbial immunity. [provided by RefSeq, Aug 2020].

Programmed Death-1 (PD-1) is a 288 amino acid type I transmembrane protein composed of one immunoglobulin (Ig) superfamily domain, a∼20 amino acid stalk, a transmembrane domain, and an intracellular domain of approximately 95 residues containing an immunoreceptor tyrosine-based inhibitory motif as well as an immunoreceptor tyrosine-based switch motif. PD-1 can be expressed on T cells, B cells, natural killer T cells, activated monocytes, and dendritic cells. PD-1 is not expressed on resting T cells but is inducibly expressed after activation. PD-1 may exert its effects on cell differentiation and survival directly by inhibiting early activation events that are positively regulated by CD28 or indirectly through IL-2. PD-1 inhibits the expression of transcription factors associated with effector cell function, including GATA-3, Tbet, and Eomes. Additionally, PD-1 ligation inhibits PI3K activity and downstream activation of Akt, as well as reduces Erk activation.

PD-1 has two ligands: PD-L1 and PD-L2. The two PD-1 ligands differ in their expression patterns. Among them, PD-1/PD-L1 axis is responsible for cancer immune escape and makes a huge effect on cancer therapy. Antibodies blocking either PD-1 or PD-L1 (anti-PD-1: nivolumab, pembrolizumab, cemiplimab; anti-PD-L1: atezolizumab, avelumab, durvalumab) are now approved by the U.S. Food and Drug Administration for treating over 20 types of cancer.

diagram PD-1

Programmed death ligand 1 (PD-L1) is the principal ligand of programmed death 1 (PD-1), a coinhibitory receptor that can be constitutively expressed or induced in myeloid, lymphoid, normal epithelial cells and in cancer. Under physiological conditions, the PD-1/PD-L1 interaction is essential in the development of immune tolerance preventing excessive immune cell activity that can lead to tissue destruction and autoimmunity. The precise and complex regulation of PD-L1 expression includes genomic alteration, transcriptional regulation, post-transcriptional and post-translational modifications, and exosomal transport.

PD-L1 acts as a pro-tumorigenic factor in cancer cells via binding to its receptors and activating proliferative and survival signaling pathways. Antibody-based PD-1-PD-L1 inhibitors can induce durable tumor remissions in patients with diverse advanced cancers, and thus expression of PD-L1 on tumor cells and other cells in the tumor microenviroment is of major clinical relevance. PD-L1 expression is an immune evasion mechanism exploited by various malignancies and is generally associated with poorer prognosis. Inhibiting PD-L1 expression in tumor cells enhances immunosurveillance and reduces PD-L1-driven non-immune checkpoint function that attenuates DNA damage response and repair. Downregulating PD-L1 expression on the antigen-presenting cells and dendritic cells enhances the response rates to immune checkpoint blockade combination therapy. Based on the key role of PD-L1 in immuno-oncology, anti-PD-L1 agents have gained momentum as novel anticancer therapeutics, by inducing durable tumour regression in numerous malignancies including metastatic lung cancer, melanoma and many others.