Date of Award

1-1-2017

Embargo Period

1-1-2023

Document Type

Dissertation - MUSC Only

Degree Name

Doctor of Philosophy (PhD)

Department

Microbiology and Immunology

College

College of Graduate Studies

First Advisor

Jennifer Wu

Second Advisor

James Cook

Third Advisor

Bei Liu

Fourth Advisor

Chrystal Paulos

Fifth Advisor

Mark Rubenstein

Sixth Advisor

Christina Voelkel-Johnson

Abstract

Proper recognition of tumor cells as targets by natural killer cells requires optimal signaling from activating receptors including NKG2D through detection of surface tumor-derived ligands. Shedding of these ligands, however, is one mechanism by which tumors cells can escape immunosurveillance to promote cancer progression. Recently, our laboratory has discovered that this escape also causes defects in NK homeostatic maintenance in the periphery. We hypothesized that soluble and membrane-bound NKG2D ligands, particularly MICB, confer differential effects on NK cell survival and function, and can be rescued with synergistic NK-potentiating treatments. We demonstrated that in the presence of tumor-derived soluble MICB, NK cells upregulate PD1 and are more susceptible to apoptosis, while stimulation with membrane-restricted MIC or neutralization of MIC leads to increased IFNγ production as well as increased phosphorylation of survival mediators AKT and STAT5. We also demonstrated that NK cells exhibit increased mitochondrial reactive oxygen species and decreased mitochondrial membrane potential in the presence of tumor-derived soluble MIC. Furthermore, we demonstrated that NK cell dysfunction in the presence of tumor-derived soluble MIC is dependent on intact PD-1 pathway signaling. In an in vivo correlate, we explored various therapy models combining neutralization of tumor-derived soluble MIC with other currently available immunotherapies, including PD-1 pathway blockade, IL-15 administration, and adoptive T cell transfer. We found that in each of these models, addition of sMIC-neutralizing therapy resulted in enhanced cooperative effects as established by concurrent potentiation of NK, CD4, and CD8 populations. In addition, we demonstrated that intact peripheral NK populations are required for optimal efficacy of these treatment regimens. Our findings provide a rationale for the targeting of tumor-derived soluble MIC to augment anti-tumor responses elicited by other viable therapies.

Rights

All rights reserved. Copyright is held by the author.

Download

Share

COinS