الفهرس 
IntroductionOnly 14 pages are availabe for public view
 |  | from | 291 |  |  |
| | | from | 291 | | |
Abstract
The innate and adaptive immune cells are mainly referred to be contrasting, separate arms of the multitude effect, the two arms basically act together, whereas cellular components of the innate arm initiate the activation process of antigen specific cells of the adaptive arm. Indeed, the original activation of the adaptive immune responses is based on robust innate immune responses. For instance, the immune responses against tumors are mainly represented and mediated by T cells of both types. At the time CD8+ cytotoxic T lymphocytes (CTLs) acts for direct killing, CD4+ T cells performs a core helper function. Both types of T cells exist as inactive form precursors in the peripheral system and must be activated to develop cytotoxicity upon infection. In addition to the effector cells, myeloid derived suppressor cells (MDSCs), and T regulatory (Treg) cells recently got much focus, as two of the key immune cellular elements creating immunosuppressive microenvironment and promoting tumor progression. Presence of both cells is considered one of the important mechanisms by which cancer cells evade the host effective immunosurveillance. Interaction of MDSCs with CD8+ cells results in the tolerance of T-cell mediated cytotoxicity, whereas tumor cells can escape the attack of the immune system. At the molecular level, it has been recently shown that the small sequences of microRNAs (miRNAs) could control immune escape mechanisms used by the tumor cell in many types of solid tumors as well as hematological malignancies including leukemia. A set of miRNAs protects cancer cells from immune clearance by reducing the immunogenicity of tumor cells and downregulating the strength of anti-tumor immune response. On the other side, another set of miRNAs strengthens anti-tumor immunosurveillance. MiRNAs derived from the tumor cells not only target these cells but also largely control various immune components including MDSCs, Treg cells, DCs, NKs, as well as B cells, CD4+ helper and CD8+ cytotoxic T cells, via intercellular communication between these cells. Previous studies have reported that miRNAs in addition to long non-coding RNAs (lncRNAs) could be used as potential molecular biomarkers for diagnosis and prognosis of different types of cancers. In addition, several studies have discussed the functional role of miRNAs in regulating the development and function of different immune cells, and the association of abnormal expression of miRNA with immune system disorders. Indeed, suppression of immune responses could be resulted from dysregulation of the miRNAs related to one or more immune-related pathway in TME. Thus, the present study aimed to analyze the expression profile of miRNAs in B-ALL pediatric patients, and to explore the role of the dysregulated miRNAs in regulation of the immune related pathways. This study also aimed to hint if any of those dysregulated miRNAs could be used as a novel molecular biomarker to prevent the immune suppression in ALL. In the present study, Affymetrix microarray platform was used for global miRNA profiling, and quantitative real time PCR (qRT-PCR) platform was used for validation of the hot spot miRNAs in B-ALL pediatric patients before, during, and after induction of chemotherapy as compared to the healthy control donors. Bioinformatics analysis was performed on immune cells-related dysregulated miRNAs, and miR-Pathway analysis was performed to explore the targeted immune-related pathways. The analysis showed that 516 miRNAs were dysregulated in B-ALL patients as compared to the healthy donor. Among them, 314 miRNAs were upregulated vs. 202 miRNAs were downregulated. In the early diagnosed patients, there were 592 dysregulated miRNAs; 328 miRNs were upregulated vs. 264 miRNAs were downregulated. In the patients who were undergoing induction of chemotherapy, there were 793 dysregulated miRNAs; 498 miRNs were upregulated vs. 295 were downregulated. In patients after induction of chemotherapy, there were 588 dysregulated miRNAs; 392 miRNAs were upregulated vs. 196 miRNAs were downregulated. In addition, miRNA profiles were analyzed for each immune effector and/or immunoregulatory cell type. On the other hand, miRNA/pathway analysis was performed to explore the implicated immune-related pathways in ALL. The analysis showed that multiple immune-related pathways were implicated and targeted by the interaction of miRNAs related to one or more of immune cells. Those pathways including TCR, Rap1, FoxO, Wnt, Hippo, TNF, mTOR, PIK3-Akt, TGF-β and Ras. Moreover, qRT-PCR analysis was performed on certain immune-related miRNAs to validate the miRNAs expression profile, and to investigate the consistency between the Microarray and the qRT-PCR platforms, in terms of miRNA expression and dysregulation status in B-ALL patients as compared to the healthy donors. The qRT-PCR analysis of miRNAs expression was found to be in line with the microarray analysis in terms of dysregulation status “regardless the trend”. This study summarized the most dysregulated miRNAs in B-ALL Egyptian patients in addition to the potential role those miRNAs in the one or more of the immune-related pathways. In addition, this study opens new avenues for testing those miRNAs as molecular biomarkers for the immunosuppressive tumor microenvironment.