Tumor-associated antigen-based immunotherapy in pancreatic cancer

To date, the clinical interventions for patients diagnosed with pancreatic cancer have not proven to be sufficient to suppress tumor growth or improve patient survival rates. Accordingly, the aim of this thesis is to illustrate the potential efficacy of an immunotherapeutic approach, focusing on anti-tumor vaccination based on tumorassociated antigens (TAA), as a promising avenue for improving the impact of future treatments for pancreatic cancer. It has been demonstrated that TAA, most notably alpha-enolase (ENO1), represent promising targets for cancer vaccines, as they elicit a robust anti-tumor response. Nevertheless, pancreatic cancer is characterized by a strong immunosuppression that represents a significant challenge to the efficacy of immunotherapy, thus breaking this condition with combinatorial approaches is of relevance. The first part of the thesis is focused on examining the impact of DNA vaccination targeting ENO1 in preclinical models, along with the development of strategies to enhance this approach. Two strategies will be discussed in this thesis: the first approach entails the combination of ENO1 DNA vaccination with a pharmacological approach targeting the inhibition of myeloid cell-mediated immune suppression with a PI3Kg inhibitor (published paper), while the other involves the optimization of the ENO1 DNA vaccine through the identification of the most immunogenic epitopes of ENO1 with the aim of triggering a more robust and “focused” anti-tumor response. The findings of this study led to the development of the next generation ENO3PEP DNA vaccine, which has been patented and whose effects on preclinical models has been investigated. The second-generation ENO3PEP DNA vaccine was shown to be more effective than the first-generation ENO1 DNA vaccine, inducing an integrated cellular and humoral response, leading to a reduction in pancreatic cancer lesions and promoting the recruitment of anti-tumour immune cells in situ, which were more activated by a stronger antigen presentation. (manuscript in preparation). The second part of the thesis focuses on the role of the circulating autoantibodies against TAA underlying a specific anti-tumor immunity, which may facilitate the identification of patients eligible for TAA-based DNA vaccination (published paper) and examines how chemotherapy influences TAA specific T cell anti-tumor response, gene expression profile and antigen receptor repertoire (manuscript under revision). The last part of the thesis presents a study published on Nature arising from external collaborations, which investigates the pathogenic role of a subpopulation of IL-1bexpressing macrophages in the progression of pancreatic cancer.