However, as described above, MHC-I downregulation is frequent in human tumors. strong class=”kwd-title” Keywords: PD-1, PD-L1, checkpoint blockade, MHC class I, tumor escape, cancer immunotherapy, biomarker, interferon gamma 1. Introduction The blockade of inhibitory immune checkpoints with monoclonal antibodies contributed to the revival of interest and belief in cancer immunotherapy. After pioneering studies with a cytotoxic T-lymphocyte associated antigen 4 (CTLA-4; cluster of differentiation (CD) 152) blockade that resulted in the Food and Drug Administration (FDA)s approval of ipilimumab for the treatment of advanced melanoma in 2011, programmed cell death protein 1 (PD-1; CD279)/PD-1 ligand 1 (PD-L1) signaling is in the focus of the current research on, and the development of, anti-tumor therapy in this field. This is because the blocking of PD-1 or PD-L1 molecules exhibited higher efficacy and lower toxicity for several types of human cancers, including melanoma, non-small Rabbit Polyclonal to RAB11FIP2 cell lung cancer (NSCLC), and renal cell cancer (RCC). However, most patients did not respond to the PD-1/PD-L1 blockade, and secondary resistance to this treatment developed in some patients. The mechanisms implicated in this failure are being Lomitapide gradually uncovered, but the biomarkers predicting successful therapy with PD-1/PD-L1 monoclonal antibodies still have not been satisfactorily revealed. The effect of the PD-1 receptor inhibition is usually attributed to the activation of cytotoxic T lymphocytes, and their direct killing of tumor cells producing major histocompatibility complex class I (MHC-I) molecules. Surprisingly, while MHC-I downregulation is one of the most frequent mechanisms of tumor escape from the hosts immune system, little attention has been devoted to surface MHC-I expression in studies of the PD-1/PD-L1 blockade. In this review, we will deal with the relationship between the inhibition of PD-1/PD-L1 signaling and MHC-I expression, and suggest a possible use of the PD-1/PD-L1 blockade for tumors with a reduced MHC-I expression. 2. PD-1/PD-L1 Signaling The PD-1 receptor is an immune checkpoint that limits the activity of immune cells in peripheral tissues, and thus prevents the development of autoimmune reactions. PD-1 was identified in association with programmed cell death in T-cell hybridoma , and its function was mainly investigated in T lymphocytes, but it is also expressed in B, natural killer (NK), and NKT cells, as well as dendritic cells (DCs) and macrophages . PD-1 is definitely absent or lowly indicated in resting na?ve or memory space T cells, but upon the activation of a T-cell receptor (TCR), it is upregulated in about six hours . In tumors, PD-1 is definitely highly indicated in dysfunctional/worn out effector T cells (both CD8+ and CD4+) and regulatory T cells (Treg) . PD-1 is definitely a monomeric type I transmembrane protein that belongs to the immunoglobulin (Ig) superfamily, and is composed of an extracellular part comprising an IgV-like website, a transmembrane website, and a short cytoplasmic tail with an immunoreceptor tyrosine-based inhibitory motif (ITIM) and an immunoreceptor tyrosine-based switch Lomitapide motif (ITSM). PD-1 engagement prospects to the phosphorylation of these motifs and the recruitment of the Src homology region 2 domain-containing phosphatase 1 (SHP-1) and SHP-2 , which inhibits the TCR/CD28-mediated activation of phosphatidylinositol 3-kinase (PI3K) from the dephosphorylation of CD3 molecules. Therefore, PD-1 engagement directly inhibits effector T-cell processes and functions, including proliferation, survival, glucose uptake, cytokine production, and cytotoxicity. PD-1 binds two ligands from your B7 family: PD-L1 (B7-H1, CD274)  and PD-L2 (B7-DC, CD273) . While PD-L1 is definitely widely indicated constitutively both on hematopoietic cells (including macrophages, DCs, and B and T cells) and nonhematopoietic cells (e.g., epithelial and endothelial cells), PD-L2 manifestation is restricted to immune cells (macrophages, DCs, and mast cells) . Lomitapide PD-L1 is also regularly indicated on tumor cells on numerous malignancies . While PD-L1 manifestation is definitely significantly correlated with a poor prognosis in individuals with different types of tumors, including renal, gastric, urothelial, ovarian, hepatocellular, pancreatic, and esophageal malignancy, there is an inverse correlation in Merkel cell carcinoma and breast tumor. In lung carcinoma, colorectal malignancy, and melanoma, both worse and better prognoses were associated with PD-L1 manifestation. The inconsistency of the prognostic value of PD-L1 could stem from technical issues of the immunohistochemical (IHC) detection of PD-L1, and temporal and spatial factors that can be affected by the heterogeneity of PD-L1 manifestation in tumors . Two mechanisms for PD-L1 upregulation in malignant cells have been explained [11,12]. First, an intrinsic (innate) resistance is definitely caused by constitutive PD-L1 manifestation in tumor cells that can be induced by oncogenic signaling pathways activated in different tumors, such as PI3K/AKT [13,14], transmission transducer and activator of transcription (STAT)-3 , epidermal growth element receptor (EGFR) , cyclin-dependent kinase 5 (Cdk5) , and MYC pathways , or by genetic changes. In lymphomas, an amplification of the PD-L1 gene , or its fusion with the MHC class II transactivator.