IL17 depletion enhances the DNA vaccine efficacy in pancreatic ductal adenocarcinoma treatment

Abstract Pancreatic ductal adenocarcinoma (PDA) remains one of the most aggressive cancer with a 5-year survival rate of ~8%. PDA is considered an “immunologically-cold” tumor because of the abundant desmoplastic immune-suppressive microenvironment and low presence of neo-antigens. Moreover, it is characterised by a complex inflammatory response in which the role of the IL17 and T helper-17 remain controversial. We have demonstrated that a DNA-based vaccination strategy targeting a PDA-associated antigen, namely alpha-enolase (ENO1), significantly prolongs survival in genetically engineered mice (GEM). We have also observed that the absence of IL17 strongly modified PDA microenvironment, improving CD8 T cell recruitment. Therefore, the aim of this study is to assess the role of IL17-targeting in combination with the DNA-vaccination. GEM crossed with IL17 knockout mice (GEM/IL17−/−) were vaccinated and monitored weekly to obtain a Kaplan-Meier survival curve. GEM vaccinated in absence of IL17 showed higher level of anti-ENO1 antibodies and IFNγ-secreting ENO1-specific T cells. The analysis of the tumor infiltrating cells revealed an increase of antigen-presenting cells and effector/memory T cells. To translate the experimental model into a clinical setting, mice orthotopically injected with PDA cells, were treated with anti-IL17 mAb in combination or not with ENO1-DNA vaccine. Only the combination elicited a significantly reduction in tumor growth that paralleled the induction of cytotoxic T cells not observed after ENO1-vaccine or anti-IL17 Ab alone. Overall, the depletion of IL17 opens new possibilities for combination to design more effective immunotherapeutic strategies to be associated with conventional one.