Date Approved

5-16-2022

Graduate Degree Type

Thesis

Degree Name

Biomedical Sciences (M.H.S.)

Degree Program

Biomedical Sciences

First Advisor

Kristin R. Renkema

Second Advisor

Christopher Pearl

Third Advisor

Frank Sylvester

Academic Year

2021/2022

Abstract

Cancer immunotherapy research is traditionally conducted with specific pathogen-free (SPF) mice, which most accurately mimic the immune system of a human newborn. This makes translational research challenging, as this mouse model is not an accurate reflection of the adult patients who ultimately receive newly developed treatments. It is necessary to further develop a mouse model that bridges this gap and increases translatability of current cancer immunotherapy research.

By cohousing specific pathogen-free mice with regular pet store (PS) mice, we have generated a cohoused (CoH) mouse that reflects the microbial experience of an adult human immune system. We investigated antigen experience, differentiation, and cytotoxicity of CD8+ T cell populations within the tumor microenvironment of both SPF and CoH mice by injecting them with B16-melanoma. We also investigated the impact of microbial experience on PD-1 expression. Increased PD-1 expression indicates a state of T cell exhaustion and may act to modulate the efficacy of anti-PD-1/anti-CTLA-4 immunotherapies. This efficacy was tested with a novel in vitro checkpoint blockade assay.

Here, we show that CoH mice exhibit significantly increased populations of antigen experienced, differentiated, and cytotoxic CD8+ T cells in blood, spleen, tumor-draining lymph nodes, and tumor. CD8+ T cells of CoH mice also exhibit significantly increased PD-1 expression and slight increases in the efficacy of in vitro anti-PD-1 immunotherapy. Most importantly, our data show that CoH mice have superior anti-tumor immunity as evidenced by their significantly lower tumor weights when compared to the larger tumors of SPF mice. Taken together, our results show that microbial experience increases cytotoxicity of tumor-infiltrating CD8+ T cells and controls tumor growth.

Available for download on Tuesday, May 23, 2023

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