Using HLA-E Expression and CREB1 Modulation to Study the Regulation of NK Cell-Mediated Cytotoxicity in Multiple Myeloma
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Date
2024-05
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The Ohio State University
Abstract
Multiple myeloma (MM) develops in the bone marrow from normal plasma cells, reshaping the bone marrow microenvironment to survive. Several MM treatments, such as immunomodulatory drugs and proteasome inhibitors, are available as therapeutic options for patients; however, MM remains largely incurable. While patients undergoing treatment may notice improvement in their symptoms, many patients still experience relapse. For that reason, personalized therapeutic options that consider genetic and environmental factors may facilitate improved patient health outcomes. While the immune system’s surveillance is equipped with the necessary mechanisms to ward off infections and diseases, cancer cells have novel ways to evade detection. The innate immune system utilizes natural killer (NK) cells to prevent the spread of viruses and growth of tumor cells. NK cells display both activating and inhibitory receptors in which, upon ligand interaction, leads to downstream signaling to elicit the proper cellular response. HLA-E, a non-classical major histocompatibility complex, is a ligand that binds to the NKG2A/CD94 inhibitory surface receptor on NK cells where it can regulate cell-mediated cytotoxicity. In healthy cells, HLA-E functions to prevent NK cell-mediated cytotoxicity upon interaction as a means of recognizing “self” cells from aberrant cells. However, as our study emphasizes, MM cells express abnormally high amounts of HLA-E to bypass the immune system and escape NK cell-mediated lysis. Our study aims to investigate immune escape via modulation of the HLA-E antigen both at the mRNA and protein level through IFN-gamma expression, proteins involved in the JAK-STAT pathway, and the CREB1 gene wherein inhibition of CREB1 has demonstrated downregulation in HLA-E and consequently restored NK cell-mediated lysis.
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Keywords
Thesis, Undergraduate, Multiple Myeloma, NKG2A/CD94, HLA-E, CREB1 inhibitor