الفهرس 
Title pageOnly 14 pages are availabe for public view
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Abstract
In recent years, an intense focus has been given to the field of immunometabolism, by which we mean the intracellular metabolic changes affecting immune cells’ fate and functions. Altered metabolic pathways have been implicated in multiple pathological processes including malignant transformations, immune-evasion of tumor cells, immune suppression as well as resistance of tumor cells towards cytotoxic drugs. Furthermore, metabolic rewiring has been observed in most tumor cells, including leukemia.
CLL is the most common type of leukemia among adults. With advances made in immunotheraprutic era, targeting aberrant metabolism in leukemic cells represents a promising approach to treat chemo-resistant CLL cells.
Enhanced aerobic glycolysis is one of the metabolic pathways conferring leukemic B-cells a metabolic plasticity that supports their survival in different body niches. Activation of BCR signalling along with microenvironmental signals result in activating mTOR-HIF-1alpha pathway which plays a fundamental role in high glycolytic capacity observed in CLL cells.
Preliminary studies on TLRs agonists in CLL showed promising results in the form of enhanced immunogenicity and apoptosis of leukemic B cells. Regarding immunometabolism, TLR7/8 agonist was found to affect the metabolism of several immune cells such as DCs and Treg cells. However, targeting the metabolism of normal or leukemic B-CLL cells with TLR7/8 agonist still represents a novel research point.
In the current study, we investigated the effect of a TLR7/8 agonist (Resiquimod) on the immunometabolism of malignant B cells in CLL patients. To verify this purpose, thirty-five individuals were recruited (20 CLL patients, 15 control). Patients were either newly diagnosed or untreated for the past three months before recruitment into our current study. Patients with other malignancies were excluded. Peripheral blood B cells, malignant and normal, were isolated using Rosettesep Human B cell Enrichment Cocktail according to manufacturer recommendation. Purified B cells were then cultured in presence and absence of TLR7/8 agonist (Resiquimod). Gene expression of mTOR and HIF-1α was assessed in harvested B cells following the aforementioned culture conditions using qRT-PCR.
Current results showed that Hb levels and platelets were significantly lower in CLL patients (p<0.001, p=0.030, respectively). While WBC count and absolute lymphocytes were significantly higher in CLL patients (p<0.001, p<0.001, respectively). CLL patients were classified according to Rai staging (low and intermediate risk=45%, high risk=55%). Immunological investigations showed no significant difference in gene expression of mTOR and HIF-1α in untreated B cells between CLL and normal groups (p=0.681, p=0.610, respectively). As for the effect of TLR7/8 agonist, gene expression of mTOR and HIF-1α decreased significantly within the same group. Treated samples of CLL patients showed a significant decrease in mTOR and HIF-1α expression (p<0.001, p<0.001, respectively). Similarly, treated samples of normal group showed a significant decrease in the expression of mTOR and HIF-1α (p=0.004, p=0.001, respectively). Referring to Rai staging, no statistically significant differences were observed between risk groups in mTOR and HIF-1α (p=0.456, p=0.603, respectively).