Browsing by Subject "IL-15"
Now showing 1 - 2 of 2
Results Per Page
Sort Options
Item Harnessing Natural Killer Cells for Improved Therapeutic Potential(2021-08) Kim, HansolCellular immunotherapy provides durable control for infected and transformed cells. However, current Natural Killer (NK) cell therapy products are limited by effector persistence. To this end, three strategies to improve the efficacy of NK cell-based therapies are discussed. Killer immunoglobulin-like receptors (KIR) are developed during maturation of NK cells. It showed that KIR develops primarily between CD56brightCD94high and CD56dimCD94high stages. Major demethylation activities were observed during the development of KIR at its proximal promoter region. Ascorbic acid showed to facilitate the development of KIR in collaboration with Ten-eleven translocation (TET) enzymes. NK cells with adaptive immunological properties persist and expand in response to cytomegalovirus (CMV) infection. The levels of intracellular metabolites were analyzed and showed that adaptive NK cells have relatively higher levels of metabolites associated with glycolysis, purine, and pyrimidine metabolism. This supports the notion that adaptive NK cells have upregulated metabolic profiles, and have capacity to expand upon reactivation of CMV which is similar to the characteristics of memory T cells. To address challenges associated with inconsistencies of the manufactured product, and treatment cost, we developed a triple gene-edited induced pluripotent stem cell (iPSC) platform for broad patient-based adoptive cell therapy. First edit is to introduce non-cleavable CD16 which prevents reduced efficacy by antibody-dependent cellular cytotoxicity (ADCC). Second edit allows iPSC-derived NK cells, termed iNK, to persist without supplementation of exogenous IL-15 by introducing IL-15 receptor fusion. The last edit was to avoid daratumumab-induced fratricide by knocking out CD38 on the surface of the iNK cells. These engineered iNK cells persisted in vivo without supplementation of exogenous cytokine and could be combined with daratumumab for enhanced treatment of multiple myeloma. The gene-edited iNK cells exhibited metabolic features and gene expression profiles similar to those of adaptive NK cells which has broad off-the-shelf potential for the treatment of advanced cancer.Item Regulation of CD8 T cell memory by ADAP(2014-12) Fiege, JessicaDuring acute infections, naïve antigen-specific CD8 T cells are activated and differentiate into effector T cells, the majority of which undergo contraction after pathogen clearance. A small population of CD8 T cells survives the contraction phase and persists as memory, to protect against future infections. Memory CD8 T cells are heterogeneous and can be found in secondary lymphoid organs (SLOs), blood and non-lymphoid tissues (NLTs). Here I demonstrate the adaptor protein ADAP enhances the formation of memory CD8 T cells in both SLOs and NLTs after pathogen challenge. ADAP-deficient memory CD8 T cells in SLOs proliferate robustly to a systemic secondary challenge. Additionally, ADAP-deficient resident memory CD8 T cells are functional in response to local peptide challenge, but only when in the presence of wild-type antigen-specific T cells. In the absence of an infection, memory-like or memory phenotype (MP) CD8 T cells can arise from homeostatic cytokine exposure during lymphopenia. In contrast to the role of ADAP after pathogen challenge, I have identified a negative regulatory role for ADAP in the formation of MP CD8 T cells in the steady state. Naïve ADAP-deficient CD8 T cells are hyperresponsive to lymphopenia in vivo and exhibit enhanced activation of STAT5 and homeostatic antigen-independent proliferation in vitro in response to IL-15. My results indicate that ADAP dampens naïve CD8 T cell responses to lymphopenia and IL-15, and demonstrates a novel antigen-independent function for ADAP in the suppression of MP CD8 T cell generation. These findings contribute to our knowledge of the generation of different memory CD8 T cell populations, and we hope to augment vaccine efficacy and better understand the formation and maintenance of memory CD8 T cells.