Gene editing of iPSC-derived natural killer (NK) cell and head and neck squamous cell carcinoma to improve NK cell anti-tumor activity
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Gene editing of iPSC-derived natural killer (NK) cell and head and neck squamous cell carcinoma to improve NK cell anti-tumor activity

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Abstract

Despite advancements in hematopoietic stem cell transplant (HSCT), graft rejection and graft versus host disease (GvHD) are leading cause of post-transplant mortality. To prevent side effects and to minimize graft rejection, glucocorticoids such as dexamethasone are often administered to patients after transplantation. However, the use of steroids suppresses the proliferation and cytotoxic function of natural killer (NK) cells. To overcome this limitation, I knocked out nuclear receptor subfamily 3 group C member 1 (NR3C1), gene that encodes for the glucocorticoid receptor, on induced pluripotent stem cell (iPSC)-derived NK cells. The NR3C1 knock out (KO) NK cells demonstrated higher proliferation in the presence of high concentration of dexamethasone in vitro while the proliferation of wild type iPSC-NK was inhibited. These studies demonstrate engineered-NR3C1 KO iPSC-NK cells can provide a novel therapeutic benefit in patients undergoing cell therapies that might involve glucocorticoid treatment to ameliorate toxicities. Even with the improvement in iPSC-NK cell therapy, tumor cells become resistant to, and escape NK cell mediated immune surveillance. Previous screening data from our group identified Charged Multivesicular Body Protein 2A (CHMP2A) as a gene that mediates tumor cell resistance to NK cell cytotoxicity. We confirmed that the deletion of CHMP2A in glioblastoma and head and neck squamous cell carcinoma (HNSCC) increased allogeneic NK cell mediated killing in vivo. Here, we better define the role of CHMP2A to regulate anti-tumor immune responses by deletion of CHMP2A in 4MOSC1 and 4MOSC2 HNSCC lines and testing these for tumor development in an immunocompetent syngeneic mouse model.

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This item is under embargo until January 11, 2024.