All ETDs from UAB

Advisory Committee Chair

Lyse A Norian

Advisory Committee Members

Lyse A Norian

Lalita Shevde-Samant

Allan Zajac

Chander Raman

Robert Sorge

Document Type

Dissertation

Date of Award

2020

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

Obesity is regarded as a major risk factor for developing renal cell carcinoma (RCC). Advanced-stage RCC exhibits chemotherapeutic resistance, but is responsive to immunotherapies such as the immune checkpoint inhibitor anti-programmed cell death-1 (anti-PD-1). Despite some clinical successes, response rates remain low for anti-PD-1 monotherapy (20-30%). Preclinical evaluations of immunotherapeutic strategies typically use lean mice and do not account for patient comorbidities. This may explain the underwhelming success rates following clinical translation of new cancer treatments. Recent studies found that obesity was associated with favorable outcomes and responses to immunotherapy in melanoma. However, the effects of obesity on anti-tumor immunity and immunotherapeutic efficacy in renal cancer remain unclear. Here, we demonstrate that diet-induced obese (DIO) mice exhibited a reduced rate of response to anti-PD-1-based combination immunotherapy, yielding distinct populations of responders and non-responders. Lean and DIO responders revealed conserved intratumoral immunogenetic and cellular profiles that were defined by favorable ratios of activated CD8 T cells to myeloid-derived suppressor cells (MDSC) and reduced PD-1 expression on CD8 T cells. Obesity-associated immunotherapy failure was in part due to heightened levels of the proinflammatory MDSC-related cytokine IL-1β. We further observed that metastatic RCC patients with obesity had reduced survival following anti-PD-1 treatment, illustrating that obesity, a state of “over-nutrition”, was associated with worse outcomes in renal cancer. Given our findings with obesity, we then pursued a complementary study examining the impact of limiting nutrient availability in the same model of preclinical renal cancer. Here, we examined acarbose, an α-glucosidase inhibitor and glucose-regulating agent used in the treatment of type II diabetes. Acarbose reduced renal tumor growth in a glucose- and CD8 T cell-dependent manner. Tumors from mice on acarbose exhibited increased frequencies of functional CD8 T cells. Importantly, in combination with either anti-PD-1 or rapamycin, acarbose led to substantial reductions in lung metastases. Interestingly, the beneficial effects of acarbose were specific to renal cancer, as a mammary tumor model did not respond to acarbose. Together, the findings from these two studies merge to demonstrate detrimental effects of obesity, and beneficial effects of the nutrient liming drug acarbose, in renal cancer.

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