Mechanism of CD8 regulation of natural killer cell biology

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Project Summary Hematologic malignancies such as acute myeloid leukemia (AML) remain clinically challenging and refractory to traditional chemotherapy approaches. For many patients, hematopoietic cell transplant (HCT) is the only curative treatment, whereby part of the efficacy is driven by donor natural killer (NK) cells that target the recipient’s leukemic cells. Natural killer cell adoptive therapy for AML patients represent a promising approach for improving patient outcomes. Work done in the Fehniger lab has defined a strategy to induce a memory-like (ML) phenotype of isolated NK cells using a stimulation with IL-12, IL-15, and IL-18 that demonstrates enhanced proliferation, cytotoxicity, and persistence both in vitro and in vivo. A phase 1 study using ML NK cells in relapsed/refractory AML patients showed approximately 50% of patients achieving a complete remission, although the mechanisms driving treatment failure are not clearly understood. Multidimensional immune correlative analysis of donor NK cells identified a negative association between CD8 expression on NK cells and treatment response. However, the role of CD8 on human conventional and ML NK cells remains unknown. The proposed project aims to understand the mechanism by which CD8 expression impacts conventional and ML NK cell biology, and has broad implications for understanding NK cell responses in cancer, infection, and autoimmunity. Preliminary data demonstrate that CD8+ NK cells have a diminished proliferative capacity compared to CD8- NK cells both in vitro and in vivo. We hypothesize that CD8 expression on donor NK cells negatively impacts overall NK cell responses against AML. Aim 1 of this proposal focuses on determining the mechanisms by which CD8+ conventional and ML NK cells have compromised proliferation, and the subsequent impact on tumor control in vivo. Specifically, the contributions of telomere length, chromatin accessibility, and metabolic differences will be investigated. Aim 2 focuses on defining the function of the CD8 molecule itself through highly efficient CRISPR-Cas9 based knockdown, and the subsequent impact on conventional and ML NK cell cytotoxicity, signaling, and survival. Together, these results will further inform future NK cell therapy designs and enhance our understanding of CD8 and its contributions to fundamental aspects of NK cell biology.