PD-1/PD-L1 expression in pancreatic cancer and its implication in novel therapies

Abstract

Pancreatic cancer is the seventh leading cause of death in developed countries and it still has a poor prognosis despite intense research in the last 20 years. Immunotherapy is a relatively new strategy in cancer treatment. The aim of immunotherapy is to block the immunosuppressive effect of tumoral cells. The PD1/PD-L1 axis has an important role in the inhibition of effector T cells and the development of regulatory T cells (Tregs). Blocking these checkpoints, and also inhibitory signals, leads to apoptosis of Tregs and increased immune response of effector T cells against tumoral antigens. Unfortunately, pancreatic cancer is generally considered to be a non-immunogenic tumor. Thus PD-1/PD-L1 inhibitors demonstrated poor results in pancreatic cancer, excepting some patients with MSI/dMMR (microsatellite instability/deficient mismatch repair). Furthermore, pancreatic cancer has a particular microenvironment with a strong desmoplastic reaction, increased interstitial fluid pressure, hypoxic conditions, and acidic extracellular pH, which promote tumorigenesis and progression of the tumor. Mismatch repair deficiency (dMMR) is correlated with a high level of mutation-associated neoantigens, most recognized by immune cells which could predict a favorable response to anti-PD-1/ PD-L1 therapy. PD-1/PD-L1 molecules could be also found as soluble forms (sPD-1, sPD-L1). These molecules have a potential role in the prognosis and treatment of pancreatic cancer.