Pancreatic cancer immunotherapy: search for new tumor antigens

Pancreatic adenocarcinoma represents one of most lethal cancer due to the lack of effective treatments. In the last 15 years a lot of efforts have been dedicated to develop alternative and adjuvant therapies for cancer and, among others, immunotherapy appears one of the most promising. Identification of tumor associated antigens is one of the key steps because it will allow their use as targets for immunotherapy and also enable quantitative monitoring of immune responses to tumor cells in cancer patients and during immunotherapeutic protocols. The newly described “cancer testis” antigen BORIS (Brother Of the Regulator of Imprinted Sites) has been recently suggested as a promising target for immunotherapy since it is over expressed at the messenger level in several tumors of different histological origin, including pancreatic adenocarcinoma. Cytotoxic T Lymphocytes (CTL) generated against BORIS protect from tumor challenge in a mouse breast cancer model and seem to be highly specific. In the first part of this study, we characterized the BORIS expression in a panel of normal and cancer tissues and cancer cell lines in order to assess its possible utilization as tumor antigen target for pancreatic cancer immunotherapy. We found that BORIS expression is not stable in the cancer cells, but depends on the microenvironment. Furthermore, we found BORIS expressed in almost all normal tissues analysed. These results taken together discourage the use of BORIS as target of an active immunotherapy. Microarray analysis of normal pancreatic tissues, compared to adenocarcinoma samples, revealed that Survivin, Mesothelin and CEACAM5 (already known to be able to elicit an immune response) are more promising candidates as target of immunotherapy because of their restricted expression in tumor. In the second part of the study, we analysed the extent of immunosuppression by analysing regulatory T cells (Tregs) from peripheral blood of pancreatic ductal adenocarcinoma patients at different stages of disease. We found an increase of Tregs in locally advanced patients as compared to healthy donors, while we noticed a decrease in the percentages of circulating regulatory T cells in metastatic patients. Since immunotherapy outcome is strictly related to the patient’s immune system functionality, an evaluation of their immunosuppression status should represent an important criterion for the enrolment in future immunotherapeutic protocols.