Abstract 4796: Treatment with chromatin remodeling agents increases MAGE-A3 expression in pancreatic cancer and enhances antigen-specific recognition by T lymphocytes

Pancreatic cancer is the fourth leading cause of cancer death in the United States and is frequently lethal despite aggressive medical and surgical treatment. Better forms of treatment are needed. One promising area of investigational treatment for patients with pancreatic cancer involves the use of immunotherapy. Approaches to cancer immunotherapy have evolved over the past 20 years resulting in improved response rates to therapy. This form of treatment was founded on the adoptive transfer of tumor-infiltrating lymphocytes in the treatment of melanoma. More recently, innovative strategies involving genetic modification of peripheral blood lymphocytes to express T cell receptors targeting tumor antigens have been developed and show promise in generating anti-tumor responses against a wide range of malignancies beyond melanoma. Vaccines and immunomodulatory agents also exist. MAGE-A3 is a cancer-testis antigen (CTA) and is expressed in up to 40% of pancreatic cancer tumors thus may be a suitable target in the treatment of this malignancy. It has a favorable expression profile, which is limited to neoplastic tissue and non-MHC bearing germ cell tissues. Furthermore, expression of MAGE-A3 (and other CTA) may be up-regulated in cancer cells by treatment with chromatin remodeling agents. Vaccines targeting MAGE-A3 are currently in use. The goal of these studies was to explore epigenetic mechanisms to enhance expression of the MAGE-A3 CTA in pancreatic cancer in an effort to improve recognition of these tumors by MAGE-A3-specific T lymphocytes as a basis for combined therapy against this disease. Pancreatic cancer cell lines were cultured with chromatin remodeling agents 5-aza-2′-deoxycytidine (5-AZA), Valproate (VALP), 5-AZA + VALP, or with the chemotherapeutic agent Gemcitabine (Gem). Expression of MAGE-A3 (and other CTA) was assayed at the mRNA or protein level. Untreated and treated pancreatic cancer cell lines were co-cultured with antigen-specific T lymphocytes (generated by transduction of lymphocytes with MAGE-A3-specific T cell receptors) and reactivity was measured via interferon gamma release. Treatment of pancreatic cancer cell lines with chromatin remodeling agents resulted in increased levels of CTAs (including MAGE-A3) and was synergistic when used in combination. The increased MAGE-A3 expression was associated with improved recognition by antigen-specific T lymphocytes. Treatment with Gemcitabine had no effect on CTA expression or antigen-specific recognition. These findings suggest that expression of CTA and MAGE-A3 in pancreatic cancer cells may be upregulated via treatment with chromatin remodeling agents, rendering them more susceptible to antigen-specific T lymphocytes. These data provide the groundwork for further studies addressing combined epigenetic therapy and immunotherapy for pancreatic cancer. 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 4796.