Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy characterized by rapid progression, invasiveness, and resistance to treatment. By using a proteome approach, we have found that protein recognized with the highest frequency by autoantibodies in PDAC sera was the alpha-enolase (ENO1), a glycolytic enzyme that also acts as a plasminogen-binding receptor. We have found that either ENO1 silencing or treatment of the PDAC cells with single administration of Adeno-Associated Virus-expressing monoclonal antibody against human ENO1 inhibited lung metastasis in immunosuppressed mice injected with PDAC cells. In addition, PDAC ENO1-silenced cells displayed a down modulated expression of cell surface molecules that regulate the adhesion to the extracellular matrix as confirmed by their reduced binding to laminin, collagen and fibronectin. ENO1 silencing in PDAC cells increased reactive oxygen species mainly generated through the sorbitol and NADPH oxidase pathways, as well as autophagy and catabolic pathway adaptations, which together affect PDAC cell growth and induced senescence. This data indicated that ENO1 plays a critical role in PDAC progression and invasion. ENO1 possesses interesting antigenic properties as it is able to elicit T cell proliferation, activation and cytotoxic specific T lymphocytes (CTL) differentiation both in vitro and in vivo. Tumor infiltrating T lymphocytes specific for ENO1 have been identified in PDAC patients and the number of ENO1-specific T cell clones generated from peripheral blood of PDAC positively correlated with a better survival. Antibody and T cell responses to ENO1 are increase in PDAC patient underwent chemotherapy. DNA vaccination to ENO1 elicits an integrated humoral and cellular immune response that was accompanied by a reduced and regulatory T cells and MDSC that significantly extends survival of Genetically Engineered Mice that spontaneously develop PDAC. Notably, mouse anti-human ENO1 monoclonal antibody inhibits MDSC adhesion to pancreatic endothelial cells and in vitro and in vivo migration and decreases MDSC arginase activity and secretion of IL-6. As whole these data demonstrate that the self-antigen ENO1 is a promising target suitable for therapeutic purposes in PDAC. In particular, the antibodies anti-ENO1 may inhibit PDA cell and myeloid cell invasion and positively modulate T cell response, making the immunotherapy more effective.
Citation Format: Francesco Novelli, Michela Capello, Michelle Chattaragada, Sammy Ferri Borgogno, Giorgia Mandili, Moitza Principe, Emanuela Mazza, Sara Bulfamante, Roberta Curto, Daniele Giordano, Paola Cappello. Targeting of alpha-enolase (ENO1) as a novel immunotherapeutical strategy for pancreatic cancer [abstract]. In: Proceedings of the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; 2016 Sept 25-28; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(11 Suppl):Abstract nr A042.
- ©2016 American Association for Cancer Research.