Mechanisms of NK cell activation and immune-editing of leukemia

PROJECT SUMMARY Candidate: Dr. Jennifer Foltz’s doctoral and post-doctoral training has focused on improving natural killer (NK) cell therapy, a type of innate lymphocyte that has shown clinical efficacy in clinical trials of acute myeloid leukemia (AML). Dr. Foltz seeks to integrate her wet-lab and computational training to delineate the mechanisms

of resistance to NK cell therapy. Her long-term career goal is to translate these findings into the clinic. Research Career Development Plan: Dr. Foltz is pursuing an independent tenure track investigator position. During this project, she will expand her expertise in genomic research and enhance her skills as a leader and

mentor, which is necessary for effectively running a research laboratory. She will attend relevant genomics and epigenomics seminars and journal clubs, participate in early investigator networking groups, leadership courses, grant writing workshops, and present her research at national and international conferences.

Research Project: The long-term goal of her proposal is to define novel mechanisms underlying the regulation of NK cell anti-leukemia function and to translate these findings into the clinic through her established collaborations. Recently, NK cell therapies have included NK cells that possess memory—the ability to

remember a prior activation, culminating in a more rapid and proficient response upon a secondary challenge. Cytokine-induced memory-like (ML) NK cells are generated through brief IL-12/15/18 activation, followed by differentiation in vitro, or in vivo within AML patients to become ML. Patients treated with ML NK cells have

improved clinical outcomes compared to cNK cells; however, not all patients respond. Based upon previous literature and our preliminary data, we hypothesize that ML NK cells exert unique immune pressure on AML driving differential AML resistance mechanisms and unique activation of ML NK versus conventional NK (cNK)

cells. This will be interrogated in the following aims: Aim 1: We will elucidate the transcription factors and epigenetic changes underlying cNK versus ML NK cell anti-leukemia functionality. Here we will determine the role of TOX, transcription factor on ML NK cell function, using CRISPR loss-of-function (LoF). We will also define

how AML modulates the epigenome of ML and cNK cells with multiomic approaches. Aim 2: We will determine how ML NK cells edit the phenotype of leukemia. Here, we will delineate how AML resistance to ML NK cells is distinct from AML resistant to cNK based upon differential KIR sensitivity and LAG-3 expression using genomic

analysis, flow cytometry, and mechanistic LoF in vitro and murine xenograft models. Together, these findings lay the groundwork for Dr. Foltz’s research career on the mechanisms underlying NK cell clinical efficacy.