Date of Award

2015

Document Type

Thesis

Degree Name

Master of Biomedical Science

Department

Microbiology and Immunology

College

College of Graduate Studies

First Advisor

Chrystal Paulos

Second Advisor

Carl Atkinson

Third Advisor

Azizul Haque

Fourth Advisor

Mark Rubinstein

Fifth Advisor

Chenthamarakshan

Sixth Advisor

Vasu

Abstract

One of the main mechanisms by which total body irradiation (TBI) enhances adoptive cell transfer (ACT) immunotherapy is by inducing systemic innate immune activation, triggered by microbial LPS released from the radiation-injured gut. Although microbial LPS is a critical mediator of TBI enhancement, it is unknown whether exogenous administration of LPS can augment therapeutic outcome. We report here that administration of LPS to non-irradiated animals did not replicate the ACT effectiveness seen in irradiated animals. In contrast, however, we found that LPS dramatically augmented ACT treatment in irradiated mice. Moreover, bacterial derived TLR agonists other than LPS (such as CpG ODN and Monophospholipid A) but not fungi- or virus-derived signals (such as PolyI:C, Zymosan, Loxoribine, and Imiquimod) improved antitumor immune responses in irradiated animals. Of clinical importance, we found that in vitro priming with LPS, CpG or MPL enhanced the anti-tumor activity of transferred CD8+ T cells. While it would be ideal to simply add TLR agonists to APCs to enhance their immunogenicity and in turn increase CD8+ T cell function, we must consider the potential negative feedback immune-regulatory mechanisms that result from TLR agonist priming, such as elevated IL-10 production. We found that transiently neutralizing IL-10 enhanced anti-tumor activity of CD8+ T-cells. However, priming CD8+ T cells with CpG ODN while neutralizing IL-10 did not augment the anti-tumor response in mice. Furthermore, we found that IL-10 was necessary to maintain IL-17 production and illicit a potent anti-tumor response in Th17 cells primed with CpG ODN.

Rights

All rights reserved. Copyright is held by the author.

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