Mechanisms of Action for Ad5-TRAIL/CpG Immunotherapy for the Treatment of Renal Cell Carcinoma

Abstract

Renal cell carcinoma (RCC) affects ~65,000 people in the U.S. annually. About 30% of RCC patients have multiple metastases at diagnosis, and an equal percentage will develop metastatic tumor recurrence after nephrectomy. Metastatic RCC is incurable, with a median survival time of only 18 months. Immune-based therapy for RCC provides the potential for long-lived protection against reoccurrence. However, even the most successful immunotherapy-based clinical trials only show objective response rates in <50% of the patients. Many factors may account for this limited clinical success, including pre-clinical use of young, normal weight ("lean") animals lacking immunomodulatory co-morbidities present in many cancer patients. Obesity is one of the main risk factors and co-morbidities for RCC. The reasons for this are likely complex and multifactorial, but generalized immune suppression during obesity may contribute to these findings. Due to the negative effects of obesity on the immune system, studies are needed to provide a framework from which novel immunotherapies can be developed for patients with metastatic RCC that is complicated by such co-morbidities. In a subcutaneous RCC model we have demonstrated that Ad5-TRAIL/CpG immunotherapy could eradicate local tumors. However, the mechanisms by which this therapy worked in a metastatic model and the negative effects obesity may exert were not known. Using a model of metastatic RCC we found that lean mice required CD8&#945;DC and pDC to mount an antitumor CD8+ T cell response capable of clearing tumors, following Ad5-TRAIL/CpG treatment. Mice complicated with diet-induced obesity (DIO) presented with immune dysregulations in both the DC and CD8+ T cell compartments. Additionally, Ad5-TRAIL/CpG therapy modulated the immunosuppressive MDSC population in lean mice, but not in DIO mice. These data correlated with the inability of DIO mice to respond to Ad5-TRAIL/CpG therapy and they ultimately succumbed to tumor burden. The research presented here highlights the immunosuppression evident in the obese environment and demonstrate the importance of examining co-morbidities, such as obesity, in pre-clinical studies for novel therapies.