Cheng, Mandy
Mandy is in the Immunity, Microbes, & Molecular Pathogenesis home area of the MBIDP. She joined the CMB training program in 2020. Her research mentor is Dr. Maureen Su. She received a B.A. degree in Molecular Cell Biology, Immunology from the University of California, Berkeley in 2017.
Mentor: Dr. Maureen Su
Natural Killer (NK) cells play a crucial role in cancer immunosurveillance by expressing multiple cell surface receptors that recognize stress-induced ligands malignant transformed cells. NK cells are the first line of defense against a multitude of cancers, much interest surrounds the potential use of CAR-transduced NK cells for cancer immunotherapy. Interestingly, dysregulation of NK cell maturation in melanoma and hepatocellular carcinoma results in tumor progression. However, the factors that regulate NK cell maturation remain unclear. Accumulating evidence suggests a critical role for epigenetic regulation in immune cell differentiation. Interestingly, our preliminary data implicate an epigenetic regulator, Ubiquitously Transcribed Tetratricopeptide repeat on chromosome X (UTX), in control of NK cell maturation and responses. Further understanding of the epigenetic modulation of NK cells in the context of low oxygen tumor microenvironments are critical to enhance the efficacy of both endogenous NK cell responses and potential NK cell cancer therapies.
Our preliminary data demonstrates NK cell-specific deletion of UTX results in abnormal proportions of NK cell maturation subsets suggesting that UTX controls NK cell maturation. Interestingly, a recent study shows UTX demethylase activity is oxygen-dependent. Moreover, aberrant growth and lack of blood supply causes many tumor microenvironments to be hypoxic. Therefore,maturation defects in response to UTX-deficiency in NK cells may be linked to the inhibition of UTX activity in a hypoxic tumor microenvironment. My project aims to work out the functional consequences of modulating UTX function in NK cells in order to help us gain a better understanding of UTX-mediated epigenetic regulation of cancer immunosurveillance in NK cells. We will test this in two ways: 1) determining the effect of UTX deletion on NK cell killing of tumor cells in hypoxic conditions in vitro and 2) using an in vivo solid tumor model, we will test the functional consequence of deleting UTX. Following these experiments, we plan to dissect the molecular mechanism in which UTX is modulating these functional responses by using RNA sequencing and chromatin co-immunoprecipitation (ChIP). These future plans will identify the specific gene loci involved in functional response modulation by UTX in NK cells. The results of this study aim to improve upon the current NK cell-based immunotherapies as well as help identify other potential targets to boost endogenous NK cell responses.
