The role of PD-1 inhibition in Pancreatic Cancer

A fundamental innovation in the treatments of advanced-stage cancers is immunotherapy in combination with immune checkpoint blockade (ICB). The encouraging anti-tumor effects of monoclonal antibodies that target immune checkpoint proteins like CTLA-4, PD-1 and PD-L1 in clinical trials have resulted in regulatory approvals for these drugs in the treatment of various types of cancers. Nevertheless, a substantial cohort of patients, in particular those with poorly immunogenic tumors and immunosuppressive microenvironment like pancreatic ductal adenocarcinoma (PDAC), don’t experience significant benefits from ICB monotherapy. This thesis will analyze studies on new predictive markers and possible strategies to enhance immunotherapy efficacy. Actually, before starting the immunological therapy, a promising predictive biomarker for PD-1 blockade therapies, such as the ratio of PD-1+ CD8+ T cells to PD-1+ regulatory T (Treg) cells in the tumor microenvironment (TME), is suggested to obtain positive response in terms of prolonged survival by patients. Different approaches have been used to set up an effective immunotherapy in different cancer types. Combination therapies in the treatment of PDAC tumours are much more efficient to sustain the activation of effector T cells (Teff) than ICB therapy alone, but also to induce the infiltration of regulators tumor-associated neutrophils (TANs) and the activation of T cells. Combined therapies may also elicit a tumor-specific immune response, activate natural killer (NK) cells and reduce the infiltration of Treg cells. Additional research and the integration of different approaches could lead to the achievement of better clinical outcomes, potentially improving the well-being of cancer patients.