Abstract 5631: Nitric oxide-based immune response modifications: A novel paradigm in tumor vaccine development against melanoma

Abstract

Abstract Although of cardinal importance, the specific role of nitric oxide (NO) in the immune response to cancer remains elusive. NO is generally considered to act as a terminal effector molecule that will promote direct cell death due to its cytotoxic and/or cytostatic properties. Conversely, NO has been also found to be associated with a cytoprotective effect due to its ability to interfere with the apoptotic machinery. We have previously shown that NO is capable to immuno-sensitized tumor cells by regulating the expression of apoptosis-related genes and modifying the structure of many protein targets. Thus, we hypothesize that NO-based modification of an autologous tumor vaccine preparation may improve the immunological priming against tumor cells and potentiate the specific anti-tumor immune response. In order to test this hypothesis we used the well-characterized B16-C57BL/6 syngeneic mouse model of melanoma. B16-F0 melanoma cells were cultured in the presence or absence of a non-cytotoxic concentration of a slow rate release NO donor for 18 hours, and later homogenized into a crude lysate. These preparations were used to vaccinate mice previously challenged with B16-F0 melanoma cells on the contralateral dorsal flank one week before, in order to frame a therapeutic paradigm of treatment in cancer. Additional doses of vaccine were applied every 7 days for a period of 3 weeks and tumor volume was determined every 3 days. Our results demonstrate that the NO-modified autologous cancer vaccine decreases the rate of tumor growth by approximately 85% (p <0.001) by day 25 when compared with the control groups. In addition, this vaccination scheme increases the survival rate by approximately 60% (p <0.001) of the experimental group when compared with controls. NO can exert a myriad of modifications at the genetic, epigenetic and post-translational level in the tumor cells promoting a robust and effective therapeutic immune response against cancer cells. Currently, we are defining the molecular and immunological mechanisms responsible for the significant increase in survival and anti-tumor immune response triggered by the NO-mediated modifications of the melanoma tumor cells. Our results suggest a new role of NO as an immune response modifier that can be exploited in cancer immunotherapy and serves as a model for vaccine development. 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 5631.