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Our understanding of the immune responses to pancreatic tumors is very limited. Analysis of the preexisting immune responses against a panel of tumor-associated antigens could help generate new immune-based therapies and diagnostic tools. Furthermore, the majority of the few studied tumor-associated antigens found in pancreatic cancer are not clinically relevant or important for cancer cell survival. Animal and clinical immunotherapeutic studies have demonstrated that there is immune selection and immune escape against most of these antigens. Overactivation of the epidermal growth factor pathway, apoptosis-related proteins and death resistance of cancer stem cells and tumor stroma have been observed in human pancreatic cancer and often are associated to overexpression or deregulation of several proteins including EGFR, Her-2, Bcl-2, survivin, Wnt-1, and Sox2. EGFR, Her-2, Bcl-2, survivin, Wnt-1, and Sox2 are implicated in tumor aggressiveness, progression, resistance, and metastasis. Overexpression of these proteins in the tumor cells and tumor stroma of advanced pancreatic cancer, and the lack of relevant mutations make them reliable targets for clinical immunotherapy trials. We designed long peptides representing immunogenic T helper and CTL epitopes for all these six proteins. The immune response was studied in pancreatic cancer (n=15), pancreatitis (n=17) and matched controls. PBMCs were analyzed to determine Th1 and Th2 immune response by production of IFN-γ and IL-10 respectively using an ELISPOT assay. Sera and ascites fluid were used for the study of the humoral immune response by ELISA using human anti-IgG and human anti-IgA. We detected significant preexisting humoral and cellular immune responses against these peptides in patients suffering from advanced pancreatic cancer. In this study, we demonstrated that this panel of proteins could be targets for humoral and cellular immune recognition in pancreatic cancer patients whereas no detectable responses were found in healthy patients. Our results suggest that a Th2 immune response is present more often in this cohort and that it could be associated with a poor prognosis measured by overall survival. In conclusion, Th2 and ascites IgA immune responses against proteins important for tumor survival that are overexpressed in cancer cells and tumor stroma were common in our cohort of pancreatic cancer patients. Some of these proteins could serve as broad-spectrum tumor antigens to target in peptide vaccine immunotherapy trials to achieve better clinically relevant responses in pancreatic cancer patients. Citation Format: Jose V. Torres, Gardner B. Murray, Ramon Cabello, Eduardo Flores, Alejandro Camacho, Pedro A. Lucero, Anton Ostashko, Roger Dela Cruz, Jr., Fernando Durazo, Xia Li, Lizette Rodriguez, Erik Ramos, Juan Pablo Marquez-Manriquez. Preexisting immune responses against EGFR, Her-2, Bcl-2, survivin, Wnt-1, and Sox2 in pancreatic cancer patients. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Progress and Challenges; Jun 18-21, 2012; Lake Tahoe, NV. Philadelphia (PA): AACR; Cancer Res 2012;72(12 Suppl):Abstract nr A54.