Date Approved

7-2020

Graduate Degree Type

Thesis

Degree Name

Biomedical Sciences (M.H.S.)

Degree Program

Biomedical Sciences

First Advisor

Kristin R. Renkema

Second Advisor

Ian Cleary

Third Advisor

Merritt DeLano-Taylor

Academic Year

2019/2020

Abstract

Immune cells, including T cells, have been used for anti-cancer therapy with varying degrees of success. One potential reason for immunotherapy failures in clinical trials may be that typical specific pathogen free (SPF) mice do not accurately replicate human microbial experience, which has important influence on shaping the adaptive immune response. Recently, several previous studies have shown that the immune system of SPF mice more closely resembles newborn human immunity, whereas immune systems from mice exposed to diverse pathogens more closely reflect adult human immunity.

To study the impact of microbial experience on the immune response, we have adopted a mouse model of microbial experience by co-housing SPF mice with mice purchased from a local pet store, therefore exposing the SPF mice to various viral, bacterial, fungal, and parasitic pathogens. Pathogen testing confirmed that the co-housed (CoH) mice are exposed to pathogens and that the SPF controls kept in the same vivarium remain pathogen-free. We used flow cytometry to show that CoH mice, but not SPF controls, also gain significantly more antigen- experienced and differentiated KLRG1hiCD44hi CD8+ T cells in blood, lymph nodes and spleen.

We injected B16 melanoma cells subcutaneously into SPF and CoH mice and monitored tumor development and T cell activation ex vivo and in vitro. CoH tumors had increased frequencies of KLRG1hiCD44hi CD8+ T cells compared to SPF tumors, and CoH tumor- infiltrating CD8+ T lymphocytes exhibited increased activation upon in vitro stimulation. Lastly, CD8+ T cells from tumors, but not spleens, of CoH mice had a higher percentage of divided cells, indicating a potentially more effective T cell phenotype.

Ultimately these findings will contribute to our understanding of how microbial experiences shape anti-tumor immunity and could have significant implications for future immunotherapy research. We hope that CoH mice, which capture more of the individual microbial variability seen in human patients, can be utilized as an additional model to improve translation from immunology and oncology research in the lab to improving success rate of human clinical trials.

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