Date of Award

5-2019

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Program

Biomedical Sciences

Track

Cancer and Developmental Biology

Research Advisor

Michael A. Dyer, Ph.D.

Committee

Terrence Geiger, Peter Murray, Marko Radic, Jeffrey Rubnitz, Paul Thomas

Keywords

Humanized mice, Neuroblastoma, NK cells, Pediatric Oncology

Abstract

NK cells are known to play an important role in the natural defense against viral infections and tumor immune surveillance. Through complex interactions between NK cell receptors and target cell ligands, transformed or unhealthy cells are identified and rapidly eliminated. NK cells have been used for therapeutic purposes in pediatric oncology, for example by harnessing the mechanisms of NK cell surveillance in acute myeloid leukemia (AML) or intervention-augmented antibody-dependent cell-mediated cytotoxicity (ADCC) in neuroblastoma. However, the underlying cellular mechanisms in these processes are not fully understood. In my thesis research, I sought to gain a deeper understanding of the molecular and cellular changes within NK cells that occur in the tumor microenvironment and with immunotherapy. I discovered that NK cells have attenuated natural cytotoxicity in children with neuroblastoma that correlates with clinical tumor response to chemoimmunotherapy. Compared to age-matched reference data in healthy children, the studied patients had higher proportions of CD56bright NK cells, suggestive of immaturity of the NK cell compartment. Although preactivation with cytokines did not entirely overcome the hyporeactivity in patient NK cells, the therapeutic use of interleukin (IL)-2 or -15 significantly enhanced the natural cytotoxicity and ADCC of tested NK cells against neuroblastoma in vitro and in vivo and therefore warrants further investigation. To provide a suitable animal model for future studies of NK cell dysfunction and immunotherapy, I developed a humanize MISTRG neuroblastoma model. Human NK cells that arise in this model after hematopoietic progenitor cell transplantation were functionally intact and capable of suppressing neuroblastoma growth with chemoimmunotherapy in vivo. Despite the discovered molecular differences of NK cell subsets in these mice compared to patient NK cells, the humanized MISTRG neuroblastoma model is a valuable tool to study NK cell biology in neuroblastoma and test whether therapeutic interventions, such as cytokine supplementation, can overcome impaired NK cytotoxicity. Collectively, results from this work are important because they link the cellular capacity of a key effector cell involved in ADCC to antibody-mediated tumor shrinkage in the clinic, revealing potential mechanisms for therapy failure in patients who receive chemoimmunotherapy for neuroblastoma.

Declaration of Authorship

Declaration of Authorship is included in the supplemental files.

ORCID

0000-0001-5143-2055

DOI

10.21007/etd.cghs.2019.0480

Additional Files
2019-002-Nguyen-DOA.pdf (367 kB)
Declaration of Authorship
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