PD-L1 gene

The PD-L1 gene is a protein-coding gene located on chromosome 9p24.1. An important paralog of this gene is PDCD1LG2. Alternative splicing leads to several transcript variants.

The PD-L1 gene encodes an immunoinhibitory receptor ligand, PDL1 aka CD274, which is expressed by hematopoietic and non-hematopoietic cells, such as T and B cells and various tumor cell types. PD-L1 is a type I transmembrane protein with immunoglobulin V-like and C-like domains. The ligand binds to its receptor PD-1. The binding of PD-L1 to the PD-1 receptor (PD-1 = acronym for "Programmed Death-1") leads to an inhibition of T-cell activation and cytokine production.

In the case of infection or inflammation of normal tissue, this interaction is important to prevent autoimmunity . In this way, the homeostasis of the immune response is maintained. In the microenvironment of tumors, however, this interaction allows tumor cells to "immune escape" by inactivating cytotoxic T cells. The expression of this gene in tumor cells is considered a prognostic factor in many types of human malignancies, including colon cancer and renal cell carcinoma.

Diseases associated with CD274 include hematologic cancers and acute lymphoblastic leukemia

In this respect, a number of checkpoint blockade inhibitors have been developed, including pembrolizumab and nivolumab, which target the PD1/PDL1 interaction. This results in T cells being able to recognize tumor cells without being deactivated by the tumor or its cytokine products

Plays a crucial role in the induction and maintenance of immune tolerance to self (Freeman GJ et al. (2000)

As a ligand for the inhibitory receptor PDCD1/PD-1, it modulates the activation threshold of T cells and limits the T cell effector response (Mezzadra R et al. 2017) Through an as yet unknown activating receptor, it can costimulate T cell subsets that predominantly produce interleukin-10 (IL10) (Dong H et al.1999). May also act as a transcriptional coactivator: In response to hypoxia, it translocates to the nucleus through its interaction with phosphorylated STAT3 and promotes transcription of GSDMC, leading to pyroptosis (Hou J et al.2020).

The PDCD1-mediated inhibitory pathway is exploited by tumors to attenuate antitumor immunity and evade destruction by the immune system, thereby facilitating tumor survival. Interaction with PDCD1/PD-1 inhibits the effector function of cytotoxic T lymphocytes (CTLs). Blockade of the PDCD1-mediated pathway leads to reversal of the exhausted T cell phenotype and normalization of the antitumor response, providing a rationale for cancer immunotherapy .

1. Dong H, Zhu G, Tamada K, Chen L. B7-H1, a third member of the B7 family, co-stimulates T-cell proliferation and interleukin-10 secretion. Nat Med. 1999 Dec;5(12):1365-9.
2. Freeman GJ et al. (2000) Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation. J Exp Med 192:1027-1034.
3. Hou J et al.(2020) PD-L1-mediated gasdermin C expression switches apoptosis to pyroptosis in cancer cells and facilitates tumor necrosis. Nat Cell Biol 22:1264-1275.
4. Mezzadra R et al. (2017) Identification of CMTM6 and CMTM4 as PD-L1 protein regulators. Nature 549: 106-110.