Interleukin 17A as a Regulator of Fibroblast–Extracellular Matrix Crosstalk and Immune Suppression in Pancreatic Cancer

Pancreatic Ductal Adenocarcinoma (PDA), representing the 90% of all pancreatic cancers, remains one of the deadliest cancers, being the seventh cause of cancerrelated death worldwide. It displays a poor prognosis with a five-year survival rate around 13% because of its asymptomatic onset, progression and late diagnosis1. The pathogenesis of PDA is primarily driven by the progressive accumulation of oncogenic mutations, including activating KRAS and inactivating TP53 loss of function. Current therapeutic approaches for PDA, including immunotherapy, chemotherapy, and immune checkpoint inhibitors, remain largely ineffective. Surgical resection remains the only curative intervention, although is only suitable for a limited number of patients. The limited efficacy highlights the urgent need for innovative strategies that can effectively improve clinical outcomes. PDA progression is driven not only by malignant epithelial cells but also by a complex interplay with non-tumor components, including endothelial, stromal, and multiple immune cell subsets. This cooperative interaction shapes a highly immunosuppressive and desmoplastic tumor microenvironment (TME) that severely compromises therapeutic responses. Among the numerous elements involved in the TME, Interleukin IL17A (IL17A) has emerged as a critical mediator influencing both stromal and immune compartments2. IL17A cytokine has been proved to play a pivotal role in the initiation and progression of PDA3. Furthermore, IL17A has been demonstrated to reprogram cancer associated fibroblasts (CAFs) towards a tumor-promoting phenotype4. Both genetic and pharmacological blockade of IL17A induce a substantial remodeling of the extracellular matrix (ECM) and enhance the immune infiltration, favoring cytotoxic CD8+T cells over regulatory T (Treg) cells accumulation and promoting CD80+ macrophages capable of enhancing antitumor immunity4. The aim of this thesis is to elucidate how IL17A-dependent mechanisms contribute to the reorganization of the TME, and to determine whether their inhibition can restore immune accessibility and enhance responsiveness to immunotherapeutic interventions. The results presented in this thesis are the subject of two published manuscripts and one currently in preparation. The first article employs a cutting-edge technology, the Multiplexed Imaging Mass Cytometry (IMC), to generate high-resolution spatial map of the TME in two murine PDA models, namely a spontaneous and a transplantable orthotopic ones, to compare 3 their microenvironmental architecture and their suitability for modeling PDA progression. The second study investigates the therapeutic potential of IL17A depletion in combination with a cancer vaccine, to enhance the anti-tumor immune responses. Finally, the thesis explores in depth how IL17A alters ECM structural organization and how these changes affect tumor cell behavior and invasiveness. Collectively, these findings provide mechanistic and translational evidence supporting the IL17A targeting as a promising strategy to reprogram the PDA microenvironment and potentiate antitumor immunity