Abstract LB-459: Altered DC function during diet-induced obesity decreases the efficacy of antitumor immunotherapy
Authors: Lyse A. Norian, Tamara A. Kucaba, Britnie R. James, Thomas S. Griffith
Journal: Cancer Research (2011)

Abstract Obesity is a mounting health concern in the United States, and the numerous physiological changes that develop with obesity can directly and indirectly affect the immune system. Among the variety of obesity-induced alterations within the immune system, there is an increased risk for cancer development, accelerated rate of tumor outgrowth, and diminished ability to generate antitumor immunity. Given the number of adults affected by obesity and the paucity of data on the confounding effects of obesity on the efficacy of immunotherapy in cancer patients, more research is needed in this area. Instead of using a genetically-induced mouse model of obesity, we used a diet-induced obesity (DIO) model where mice were fed normal chow or high-fat feed for 20 weeks. Diet-induced obesity in mice represents a clinically-relevant model of obesity, accompanied by increased leptin production and systemic inflammation. For our studies, mice fed high-fat feed were considered obese if their body weight was &amp;gt;3 S.D. above the mean of age-matched mice fed normal chow (normal weight; NW). As dendritic cells (DC) are critical regulators of antitumor immunity, we examined the combined effects of obesity and tumor outgrowth on DC function to test the hypothesis that when compounded by obesity and its associated chronic inflammation, DC function and the generation of T cell-mediated antitumor immunity after the initiation of immunotherapy would be profoundly decreased. Using NW and DIO mice, we evaluated DC function in mice bearing orthotopic renal cell carcinoma tumors and tumor-free controls. DIO mice had profoundly altered serum cytokine and chemokine profiles, with upregulation of 15 proteins, including IL-1α, IL-15, IL-17, and LIF. Tumor-free DIO mice had similar percentages of conventional splenic DC compared to NW counterparts; however, DC from DIO mice had a reduced T cell stimulatory capacity. Further analysis revealed that the kidneys of tumor-free NW and DIO mice had similar percentages of DC, but RCC growth led to greater local DC infiltration in DIO mice. Interestingly, the DC from DIO tumor-bearing kidneys actually suppressed T cell proliferation ex vivo when co-cultured with peptide-pulsed stimulatory splenic DC from NW mice. Following administration of a DC-dependent immunotherapy (Ad-TRAIL/CpG), established RCC tumors regressed in NW mice. Strikingly, the same immunotherapy was ineffective in DIO mice, and was accompanied by decreased CD8 T cell infiltration into tumor-bearing kidneys and increased local infiltration of DC. Our results show that obesity produces unique alterations in DC function in the presence and absence of tumor growth, and impairs the efficacy of DC-dependent antitumor immunotherapy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr LB-459. doi:10.1158/1538-7445.AM2011-LB-459