Background: Pancreatic ductal adenocarcinoma (PDA) is one of the most lethal cancer, both for lack of effective screening method and for resistance to chemotherapy (CTX) and radiotherapy. However, some chemotherapeutic agents, such as gemcitabine, have immune modulatory effects. We started from the hypothesis that more immunogenic antigens can be induced by CTX and targeted by passive or active immunotherapy. To discover TAAs that might be selected for immunotherapy, antibody response in PDA patients' sera was analyzed before and after CTX. TAAs mostly recognized after CTX were selected and used to evaluate whether PDA patients' T cells have an increased TAA-specific response after CTX and if the immune checkpoint blockade (ICB) could enhance T cells activation.
Material and methods: Antibody response in sera of PDA patients, before and after CTX treatments, was analyzed by Serological Proteome Analysis (SERPA) and the antigens recognized were identified by mass spectrometry. T cell proliferation and IFNγ and IL10 production were evaluated on patients' PBMCs (peripheral blood mononuclear cells) stimulated with TAAs in presence or not of ICB.
Results: After CTX the level of antibody recognition increased, both in term of intensity and number of recognized TAAs. For some of these TAAs the increased antibody recognition showed a positive correlation with patients' survival. Of note, after CTX an increased complement dependent cytotoxicity against PDA cell lines was demonstrated in 48% of PDA patients' sera. In most cases after CTX PDA patients' T cells stimulated in vitro with recombinant selected TAAs proliferated more. Moreover, about 50% of TAA-specific T cell responses switched from a protumor regulatory to an antitumor effector phenotype after CTX. Interestingly, this shift was better elicited by ICB after CTX than before.
Conclusions: These data indicate that in PDA patients CTX induces an increase of TAAs-specific antibodies. Furthermore, CTX can switch several TAA-specific T cell responses from regulatory to effector phenotype and ICB could potentiate this polarization. Based on these results the combination of DNA vaccination against TAA and CTX is currently investigated in a PDA mouse model.
Citation Format: Sara Bulfamante, Giorgia Mandili, Moitza Principe, Daniele Giordano, Emanuela Mazza, Claudia Curcio, Laura Follia, Giulio Ferrero, Andrea Evangelista, Maria Antonietta Satolli, Paola Cappello, Francesco Novelli. Antibody and T cell response profiling in pancreatic cancer patients before and after chemotherapy identify tumor associated antigens suitable for immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2761.