Abstract 401: Inducible nitric oxide synthase suppresses the expression of CXCL10 and hence leads to the poor outcome of Stage III malignant melanoma

Abstract

Abstract Melanoma is the deadliest form of skin cancer and exhibits extremely aggressive growth characteristics. Accumulating evidence suggests that melanoma is heterogeneous in response to therapies as well as etiology, survival with advanced disease, and tumor mutational status. Our previous studies showed that the expression of inducible nitric-oxide synthase (iNOS) in melanoma tumor cells strongly correlate with poor patient survival. We are hypothesizing that iNOS is a key molecule in melanoma signature comprising an inflammatory microenviroment of poor outcome. To gain further insight into the nature of the melanoma inflammatory microenvironment, PCR array related to inflammatory and autoimmunity gene was done on a series of Stage 3 melanoma lymph node metastases samples to compare the gene expression level directly between iNOS-positive and -negative tumor samples. As a result, we found the significant correlation between iNOS expression and suppression of CXC Chemokine ligand 10 (CXCL10) in mRNA and protein levels. In the set of 16 cases of Stage3 melanoma samples, high CXCL10 expressing group showed the favorable prognosis compared to low CXCL10 expressing group. In the further in vitro analysis, we found that nitric oxide (NO) provided by S-nitroso-N-acetyl-l,l-penicillamine suppresses the expression of CXCL10 in iNOS negative and CXCL10 positive melanoma cell. Quenching the NO with NO scavenger, 2-(4-Carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide in iNOS positive and CXCL10 negative cell lines induces the expression of CXCL10. CXCL10 is reported to play the role in the recruitment of cytotoxic immune cells such as CD8+ T cells, and NK cells into the tumor microenvironment. CXCL10 also has a function of antagonizing the activities of angiogenic factors such as bFGF and IL-8 and it is considered as an anti-tumorigenic protein. Our study suggests that production of NO by iNOS inhibits the expression of CXCL10 in melanoma and comprises the pro-tumorigenic tumor microenvironment. Inhibition of NO may have a possibility to render the tumor microenvironment to anti-tumorigenic status. Therefore, iNOS will be a good target in the treatment of melanoma. 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 401. doi:10.1158/1538-7445.AM2011-401