In-vitro Modulation of mTOR-HIF-1α Axis by TLR7/8 Agonist (Resiquimod) in B-Chronic Lymphocytic Leukemia

• Published in: Indian journal of hematology & blood transfusion Vol. 39; no. 4; pp. 537 - 545
• Main Authors: Hanafy, Rana M., Demian, Soheir R., Abou-Shamaa, Lobna A., Ghallab, O., Osman, Eman M.
• Format: Journal Article
• Language: English
• Published: New Delhi Springer India 01-10-2023; Springer Nature B.V
• Subjects: Blood Transfusion Medicine; Gene expression; Hematology; Human Genetics; Leukemia; Medicine; Medicine & Public Health; Metabolism; Oncology; Original; Original Article; Targeted cancer therapy; mTOR; Immunometabolism; HIF-1α; B cells; TLR7/8 agonist; B-CLL
• ISSN: 0971-4502; 0974-0449; 0974-0449; 0971-4502
• DOI: 10.1007/s12288-023-01649-y

Targeting toll-like receptors (TLRs), via TLR agonists, has been implicated in the regulation of immunometabolism. B-chronic lymphocytic leukemia (B-CLL) represents a suitable model for B-cell derived malignancies with shifted metabolic adaptations. Several signaling pathways have been found to be critical in metabolic reprogramming of CLL, including mechanistic target of rapamycin- hypoxia inducible factor-1α (mTOR- HIF-1α) pathway, the main metabolic regulator of glycolysis. Here, we investigated the effect of TLR7/8 agonist (Resiquimod) on the expression of mTOR and HIF-1α in patients with CLL. B cells were purified using Rosettesep Human B cell Enrichment Cocktail (Stem cell Technologies, Vancouver, BC, Canada#15,024) from peripheral venous blood of CLL patients (n = 20) and healthy individuals (n = 15). Isolated B cells were then cultured in both presence and absence of Resiquimod. Gene expression of mTOR and HIF-1α were assessed using qRT-PCR. Resiquimod significantly decreased mTOR and HIF-1α gene expression in both CLL (
p
 < 0.001and
p
 < 0.001, respectively) and Normal B cells (
p
 = 0.004 and
p
 = 0.001, respectively). Resiquimod may reprogram immunometabolism of malignant B-CLL cells via down-regulation of key glycolytic metabolic actors, mTOR and HIF-1α genes. Accordingly, Resiquimod may be an adjuvant as a therapeutic tool for CLL, which needs to be studied further.