Date on Master's Thesis/Doctoral Dissertation

8-2018

Document Type

Doctoral Dissertation

Degree Name

Ph. D.

Department

Microbiology and Immunology

Degree Program

Microbiology and Immunology, PhD

Committee Chair

Egilmez, Nejat K.

Committee Member

Bodduluri, Haribabu

Committee Member

Dryden, Gerald W.

Committee Member

Li, Bing

Committee Member

Martin, II, Robert C. G.

Committee Member

Schmidt, Nathan W.

Author's Keywords

colon cancer; immunotherapy; T cells; nanoparticles; epithelial barrier integrity

Abstract

In this dissertation, the relationship between colon cancer and inflammation, the utility of novel imaging modalities for diagnosis of colitis and cancer, and the therapeutic efficacy of orally delivered, particle-based immunotherapy for the treatment of colon cancer are evaluated. In Chapters One and Two, multispectral optoacoustic tomography (MSOT) is demonstrated to effectively detect colon inflammation without the use of exogenous contrast prior to detection using conventional colonoscopy. Oral particle uptake is demonstrated in the distal small intestine and proximal colon, confirming site-specific delivery. In Chapter Three, administration of IL-10 and IL-12 containing particles is shown to act synergistically to significantly reduce tumor burden in the setting of established colon tumors. Cellular mechanisms deriving from effects on CD8+ T cells and T17 cells as well as a physiologic mechanism stemming from combination therapy’s strengthening of colon epithelial barrier integrity are described. In Chapter Four, the lack of efficacy of orally administered anti-PD1 therapy is demonstrated. IL-17 and γδ T cells, but not CD4+ T cells, are shown to be critical mediators of treatment failure. The significant anti-tumor effect of combination treatment with either anti-IL-17A or anti- γδ TCR and anti-PD1 demonstrate exciting therapeutic targets for future clinical trials. Finally, in Chapter Five, a clinically relevant model of colon cancer is described. This mutationally-driven model recapitulates the clinical scenario of single adenoma development, adenoma to carcinoma transition, carcinoma progression, and eventual metastasis to the liver. Such a model provides an excellent platform for preclinical evaluation of many different aspects of colon cancer.

Available for download on Thursday, February 07, 2019

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