Several companies have designed commercially available PD-L1 IHC tests, including 22C3, 28-8, SP263, SP142, E1L3N, and 73-10 assays. (1). Programmed death-ligand 1 (PD-L1), also referred to as B7-H1 or CD274, is constitutively expressed on antigen-presenting cells, lymphoid, endothelial, and epithelial cells (2). Interferon gamma (IFN-) and tumor necrosis factor (TNF-) secreted by activated T-cells can also induce PD-L1 expression on tumor cells and antigen-presenting cells (APCs) (3).Figure 1shows that nave T-cells are activated through binding between T cell receptors (TCR) and the peptide-MHC complex presented by (APC); T-cell activation can lead to transient upregulation of PD-1, which is the receptor of PD-L1. Binding between PD-1 and PD-L1 negatively regulates downstream signaling mediated by co-activation of TCR and CD28 (4). When PD-L1 interacts with PD-1, the immunoreceptor tyrosine-based inhibitory motifs (ITIM) and immunoreceptor tyrosine-based switch motifs (ITSM), which are on the intracellular domain of PD-1, can be phosphorylated. The Src homology 2 domain-containing protein tyrosine phosphatase 1 (SHP-1) and Src homology 2 domain-containing protein tyrosine phosphatase 1 (SHP-2) are then recruited and bind to ITIM to further inhibit the signaling downstream of the TCR (5). After inhibiting the TCR-mediated signaling pathway, PD-1 prevents the activation of the pathway mediated by PI3K/Akt or Ras/MEK/Erk. This further inhibits the function of CD8+ T-cells (6). Programmed cell death 1 ligand 2 (also known as PD-L2, B7-DC), which is the second ligand of PD-1, is expressed on tumor cells, APCs, cancer associated fibroblasts, and macrophages (79). PD-L2 plays an inhibitory role on Rimantadine (Flumadine) the functioning of T-cells, which is similar to that of PD-L1. Meanwhile, PD-L1 also interacts with the surface protein CD80 (B7-1) expressed on activated T-cells. Interacting with PD-L1, CD80 could induce increased expression of Bim, which contributes to the apoptosis of CD8+ T-cells (10). As a result, the PD-1/PD-L1 signaling pathway promotes tumor cells escaping immune surveillance by inhibiting cell survival and activation of T-cells. == Figure 1. == PD-1/PD-L1 or PD-1/PD-L2 in the tumor microenvironment. PD-1 is expressed on T-cells and NK cells. PD-L1 is expressed in tumor cells, antigen presenting cells, cancer associated fibroblasts, and in several immune cells (myeloid cells, endothelial cells, M2 macrophages). The binding of PD-L1 or PD-L2 to PD-1 could inhibit the functioning of T-cells and NK cells. IFN- secreted Rimantadine (Flumadine) by activated T-cells mediates the up-regulation of tumor PD-L1. The blockade of PD-1/PD-L1 or PD-1/PD-L2 interaction by PD-1 or PD-L1 inhibitors could restore T-cell or NK cell activation. Targeting PD-L1 and PD-1 interactions is a novel therapeutic strategy used for cancer treatment. Antibodies targeting PD-1 or PD-L1 have marked a breakthrough in cancer immunotherapy and have become a hot topic in cancer therapy. Many companies have therefore begun studies on cancer immunotherapy and applied a series of related patents and patent applications in this field. To date, there have been about 5,000 patents published, and the number of patents continues to increase (Figure 2). In this review, we demonstrate the development of PD-1/PD-L1 directed immunotherapy and progress in inhibitors disrupting PD-1/PD-L1 binding. Moreover, patents or patent applications related to PD-1/PD-L1 signaling pathway and its inhibitors will also Rimantadine (Flumadine) be discussed in this review, which will provide an update on PD-1/PD-L1 targeted cancer therapy. == Figure 2. == Numbers of international patent applications published per year containing the word PD-1 or PD-L1 in the title, claim, or abstract. == Historical Overview of Relevant Patents of PD-1/PD-L1 Targeting Cancer Immunotherapy == The PD-1 protein was discovered by Tasuku Honjo in 1992, and he was awarded the Nobel Prize in physiology and medicine in 2018. The patent published in 1995 by Honjo firstly proposed the sequence of PD-1 protein Rabbit Polyclonal to TPH2 (phospho-Ser19) and gene encoded PD-1 (11). Honjo’s discovery also showed that PD-1 is a protein that negatively regulates the immune system (12). Later, Gordon Freeman identified B74 as one of the ligands to PD-1 (13). Meanwhile, Dr. Lieping Chen and his team independently discovered B7-H1. The sequence of B7-H1 protein and gene encoded B7-H1 was published in 1999 Rimantadine (Flumadine) by Dong et al. (14). However, they did not mention the correlation between B7-H1 and PD-1. Based on his own findings of B7-H1, Chen et al. applied a series of patents related to B7-H1 protein. Meanwhile, in 2000, Freeman et al. published a paper mentioning that B7-4 was renamed to PD-L1 and is the same as B7-H1 protein discovered by Freeman et al. (15). Freeman also mentioned.