All ETDs from UAB

Advisory Committee Chair

Lyse A Norian

Advisory Committee Members

Chenbei Chang

Wendy Demark-Wahnefried

Douglas Hurst

Lyse A Norian

Alexander Szalai

Document Type

Dissertation

Date of Award

2020

Degree Name by School

Doctor of Philosophy (PhD) School of Health Professions

Abstract

In the US, nearly 40% of adults have obesity. Further, obesity is known toincrease the risk for development, recurrence, and mortality associated with multiple types of cancer. However, despite such high prevalence, the impact of excess body weight on anti-tumor immunity and response to immunotherapeutics remains poorly and incompletely understood. In order to address these deficiencies, we have utilized multiple approaches to study obesity-associated perturbations in the immunogenetic, soluble protein, and cellular profiles of mice bearing mammary tumors and treatment naive human subjects with clear cell renal cell carcinoma (ccRCC). In a pre-clinical murine model of breast cancer, we find that diet-induced obesity drives hyperactivation of CD8 tumor-infiltrating lymphocytes (TILs), a phenomenon characterized, in part, by high expression of the death receptor Fas. Mammary tumors from obese mice also have heightened accumulation of Fas ligand (FasL)-expressing granulocytic myeloid-derived suppressor cells (G-MDSCs). In the obese tumor microenvironment, FasL+ G-MDSCs induced apoptosis of CD8 TILs, diminishing CD8 TIL accumulation intratumorally. Elevated G-MDSC accumulation and CD8 TIL apoptosis were associated with immunotherapy resistance in obese animals. The combination of immunotherapy with CXCR2 blockade was sufficient to attenuate G- MDSC accumulation and improve immunotherapeutic response in obese mice. In contrast to our findings in pre-clinical breast cancer, profiling of peripheral blood and tumor specific anti-tumor immune responses in ccRCC subjects revealed only modest changes based on body mass index (BMI)-defined obesity. Obesity reduced the concentration of plasma IGFBP-1 and abundance of circulating classical monocytes and regulatory T cells, but had no impact on flow cytometric or expression-based leukocyte profiles in tumors. Immunogenetic and soluble protein profiling revealed few, but specific, changes to the obese tumor microenvironment, including increased expression of IDO1 and CD36 and increased intratumoral concentrations of PLGF and VEGF-A. Here, we describe for the first time that obesity enhances MDSC-mediated CD8 TIL apoptosis and immunotherapy resistance in pre-clinical breast cancer. Collectively, these studies provide much-needed insight into the impact of obesity on anti-tumor immunity and response to immunotherapy. Further, we identify targets for further prospective analyses to determine how obesity-specific changes in immune profiles may impact clinical and immunotherapeutic outcomes.

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