Abstract 4051: Protection from CTL mediated killing by iNOS expression in a mouse model of melanoma

The presence of peroxynitrite (PNT) in tumor tissue, as measured by its surrogate tissue marker, nitrotyrosine (NT), is correlated with poor clinical prognosis and poor response to immunotherapy. The production of PNT at the tissue can be attributed to multiple sources. For example, many tumors are characterized by extensive infiltration by immature myeloid cells with robust immuno-suppresive activity. These myeloid derived suppressor cells (MDSC) are known to produce high level of reactive oxygen species (ROS) and reactive nitrogen species (RNS), and the reaction of these two species is a major source of PNT at the tumor site. In addition to MDSC, iNOS expression in tumor cells themselves can act as a major source of PNT. Here we show that B16 melanoma cells are protected from CTL mediated lysis via iNOS expression. This effect is independent of effects on the T cells themselves as ability to lyse iNOS expressing and non-expressing cells was assessed in the same culture. Previously it was shown that peroxynitrite treated cells bound certain exogenous MHC class I peptides with lower affinity than their non-treated counterparts. Using a system of endogenous iNOS expression, our data supports the existence of a similar phenomenon for endogenously processed and presented peptide antigens, suggesting that the repertoire of surface bound immunogenic peptides is different in tumors when compared to the presentation of those same antigens in the tumor draining lymph node, where PNT is less prevalent. As a result, immune responses generated in the lymph node are against antigens which are not relevant and will fail to control tumor growth. Additionally, our data suggests that pharmaceutical intervention to reduce intratumoral PNT levels may buoy concurrent immunotherapy. Citation Format: Douglas M. Marvel, Dmitry Gabrilovich. Protection from CTL mediated killing by iNOS expression in a mouse model of melanoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4051. doi:10.1158/1538-7445.AM2015-4051