PD-1 and cancer: molecular mechanisms and polymorphisms.

The programmed cell death protein 1 (PD-1) is expressed by activated T cells that act as an immunoregulatory molecule, and are responsible for the negative regulation of T cell activation and peripheral tolerance. The PD-1 gene also encodes an inhibitory cell surface receptor involved in the regulation of T cell functions during immune responses/tolerance. Beyond potent inhibitory effects on T cells, PD-1 also has a role in regulating B cell and monocyte responses. An overexpression of PD-1 has been reported to contribute to immune system avoidance in different cancers. In particular, PD-1 over-expression influences tumor-specific T cell immunity in a cancer microenvironment. Blocking the PD-1/PD-1 ligand (PD-L1) pathway could potentially augment endogenous antitumor responses. Along these lines, the use of PD-1/PD-L1 inhibitors has been applied in clinical trials against diverse forms of cancer. It was believed that antibodies targeting PD-1/PD-L1 might synergize with other treatments that enhance endogenous antitumor immunity by blocking inhibitory receptor-ligand interactions. However, in all cases, the host genetic status (as well as that of the tumor) is likely to have an impact on the expected outcomes. Various investigations have evaluated the association between PD-1 polymorphisms and the risk of various types of cancer. Frequently studied PD-1 polymorphisms, PD-1.1 (rs36084323), PD-1.3 (rs11568821), PD-1.5 (rs2227981), PD-1.9 (rs2227982), and PD-1 rs7421861, and their associations in the risk of susceptibility to different types of cancer are mentioned in this review, as are studies highlighting the significance of conducting genetic association studies in different ethnic populations.

Differential expression of microRNAs in renal transplant patients with acute T-cell mediated rejection.

BACKGROUND: MicroRNAs (miRNAs) regulate most of encoding genes and protein. In this study, we aimed to investigate the expression levels of miR-142-5p, miR-142-3p, miR-155 and miR-223 in paired biopsy and peripheral blood mononuclear cell (PBMC) samples of renal allograft recipients with acute T-cell mediated rejection (ATCMR), compared with normal allografts (NA). METHODS: In this study, the expression levels of individual miRNAs were determined in biopsy and PBMC samples of 17 recipients with ATCMR and 18 recipients with NA. RESULTS: Our results showed that the intragraft expression levels of all studied miRNAs were significantly higher in ATCMR than NA. However, regarding the PBMC samples, miR-142-3p and miR-223 were significantly increased in ATCMR than NA. Receiver operating characteristic (ROC) analysis showed that miR-142-5p, miR-142-3p, miR-155 and miR-223 in biopsy samples and miR-142-3p and miR-223 in PBMC samples could discriminate ATCMR from NA recipients. CONCLUSION: It has been reported that high intragraft expressions of miRNAs have a profound role in the pathogenesis of ATCMR process. Our results showed that high expression of all the studied miRNAs in biopsies and miR-142-3p and miR-223 in PBMC samples could be used as suggestive diagnostic tools to discriminate ATCMR patients from NA.

Altered Expression of MicroRNAs Following Chronic Allograft Dysfunction with Interstitial Fibrosis and Tubular Atrophy.

Chronic allograft dysfunction (CAD) remains the major cause of renal transplant loss and characterized by interstitial fibrosis and tubular atrophy (IFTA). MicroRNAs (miRNAs) are implicated in many biological processes as well as innate and adaptive immune responses. We aimed to investigate whether CAD with IFTA is associated with differential expression of miR-142-5p, miR-142-3p and miR-211 within biopsy and peripheral blood mononuclear cell (PBMC) samples and whether expression of miRNAs are diagnostic for CAD with IFTA and predicts renal allograft function. In this study, biopsy and PBMC samples of 16 CAD with IFTA and 17 normal allografts (NA) were collected. Using Taqman MicroRNA Assays the expression levels of miR-142-5p, miR-142-3p and miR-211 were determined in two groups. Our results showed that miR-142-5p and miR-142-3p were significantly (p<0.0001) up-regulated and miR-211 was significantly (p<0.0001) down-regulated in renal allograft tissues of CAD with IFTA compared with NA recipients. Moreover, miR-142-3p and miR-211 were significantly (p<0.0001) up-regulated and down-regulated respectively in PBMC samples of CAD with IFTA. According to the ROC curve analysis, miR-142-5p in biopsy samples, but miR-142-3p and miR-211 both in biopsy and PBMC samples could be used as a diagnostic biomarker of CAD with IFTA and a prediction factor of allograft function. In this study, miRNAs were differentially expressed in the kidney allograft biopsy and simultaneously in PBMC samples of patients with CAD with IFTA. We suggest that the expression of miRNAs in PBMC might be used for monitoring the post transplantation and also as potential non-invasive biomarkers of kidney graft function and CAD with IFTA.