CCL5/CCR5 axis inhibition as therapeutic strategy for the treatment of pancreatic ductal adenocarcinoma

In the recent years, the knowledge and the research on immunotherapy has been rapidly growing, particularly in the oncology field. Immunotherapy treatment is aimed at stopping or slowing down the growth of malignant cells, preventing their metastatic spread through increased recognition by the immune system. Pancreatic Ductal Adenocarcinoma (PDAC), a devastating disease with a 5-year survival of only 10%, has been commonly defined as “immunologically cold” due to the presence of an immune-quiescent and suppressive tumor microenvironment (TME) enriched in suppressive T cell populations, with few effector T cells, leading to resistance to immunotherapies. Since only few conventional therapies have demonstrated significant improvement in the overall survival of patients, new therapeutic strategy needs to be set up, including those shaping tumor immunogenicity. Several studies have demonstrated that inhibiting infiltrating T regulatory cells (Tregs) through the modulation of chemokine signalling might be an efficient immunotherapy strategy. According to this, it has been demonstrated that CCL5/CCR5 axis induces the migration and recruitment of immunosuppressive cells as Tregs. The purpose of this thesis was to illustrate the importance of developing new effective immunotherapies against “cold” tumors such as PDAC, focusing on understanding the role and the biological effects of the CCL5/CCR5 axis in modulating PDAC immunosuppressive TME to validate its use as an immunotherapy target as part of a multi-agent treatment.