Abstract 5594: Immunotherapy of metastastic renal cell carcinoma reveals a critical role for nitric oxide expression in the control of lung metastases but not primary tumors

Abstract

Abstract Using an orthotopic mouse model of renal cell carcinoma, we showed previously that IL-2/αCD40 combination immunotherapy resulted in synergistic anti-tumor responses. In contrast, the use of either IL-2 or αCD40 as single agents mediated only partial, transient anti-tumor effects. We now show that treatment of tumor-bearing mice with IL-2/αCD40, but not either IL-2 or αCD40 alone, induces significant nitric oxide synthase (NOS2) expression within the tumor microenvironment through an interferon gamma-dependent pathway. In saline-control treated mice (low NO levels), NO inhibition reduced lung metastases by itself. However, in the context of immunotherapy (high NO levels), NOS2 inhibition completely abrogated the ability of IL-2/αCD40 treatment to reduce lung metastases but had no effect on the ability of IL-2/αCD40 to reduce primary kidney tumor burden. We further show that IL-2/αCD40 induces the NO-dependent decrease in matrix metalloproteinase (MMP) expression and activity, concomitant with an increase in the expression of tissue-inhibitor of metalloproteinase (TIMP)-1 within the tumor microenvironment. Finally, the treatment of tumor-bearing mice with the NO donor, JS-K significantly reduced lung metastases but had no effect on primary tumor size. These data distinguish the primary anti-tumor effects of IL-2/αCD40 immunotherapy, which are independent of NO expression, from the important ability of IL-2/αCD40 to inhibit lung metastases through the NO-dependent regulation of MMP and TIMP functions. Furthermore, the reduced MMP9 activity may be indicative of M1 polarized macrophages within the tumor microenvironment after IL-2/αCD40 treatment. Our data demonstrate the mechanistic basis for the IL-2/αCD40-mediated control of lung metastases and indicate that the context-dependent application of NO-inducing agents may hold considerable promise for the treatment of metastastic disease. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5594.