All ETDs from UAB

Advisory Committee Chair

Lyse A Norian

Advisory Committee Members

Andre Ballesteros-Tato

Donald J Buchsbaum

Sunil Sudarshan

Document Type

Dissertation

Date of Award

2018

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

Obesity affects ~40% of United States adults and is linked to the development of multiple health-related complications. Obesity is a major risk factor for developing renal cell carcinoma (RCC), the most common type of renal cancer. Metastatic RCC has poor five-year survivals, therefore, new, efficacious therapeutics are needed. One avenue is immunomodulation to generate tumor-specific, systemic anti-tumor responses that are long-lasting against local, metastatic, and recurrent tumors. Despite encouraging results, immunotherapeutic treatment of RCC is underwhelming. Cytokine therapies are largely toxic, while newly FDA-approved ‘checkpoint blockade’ (CB) antibodies have responses <50%. Here, we present a strategy employing a T cell priming therapy (AdTR/CpG) upstream of CB administration. Combinatorial use resulted in improved anti-tumoral immune responses, significantly reduced tumor burdens, and extended overall survival in pre-clinical RCC. Importantly, this approach was more efficacious than either single agent(s). Pre-clinical therapy development is often accomplished using lean, healthy animals–thus, to improve translatability we examined immune responses in the context of obesity as a major patient comorbidity. Subsequently, we investigated AdTR/CpG/CB in diet-induced obese (DIO) mice. Tumor/treatment-naïve DIO mice exhibited obesity-associated features; i.e., increased leptin/insulin and serum cytokines. These effects were not dependent on high-fat diet administration as mice resistant to weight gain had minimal alterations in these factors, and were similar to mice maintained on standard chow. As previously identified, 80% of DIO mice bearing renal tumors failed to respond to AdTR/CpG. AdTR/CpG/CB-treatment dramatically improved response rates against DIO tumors, however, decreased obese responder percentages were observed in both combinatorial therapies and was independent of high fat diet administration alone. Impaired response rates were not model or immunotherapy-specific as similar reductions in tumor clearance were seen in models of melanoma and sarcoma. Furthermore, responses were not due to initial T cell priming or unequal precursor CD8+ T cell frequencies. Detrimental changes in the tumor microenvironment underscored failure in obese mice and revealed therapeutic success was defined by a T cell-myeloid cell-inversion profile, supported by immunogenetic and flow cytometric analyses. Thus, we demonstrate a novel combinatorial approach for improving checkpoint-based outcomes, and identify the ability of host obesity to impede therapy-induced anti-tumor immunity.

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