Dipesh Kumar Yadav, Cai-de Lu and Rajesh Kumar Yadav
Pancreatic cancer is one of the deadliest human malignancies and little progress has been achieved in its treatment over the past decades. Historically, chemotherapy or radiotherapy did not provide significant survival benefit in advanced pancreatic cancer. Thus, new therapeutic approaches are needed. As there is strong evidence that vaccine therapy against pancreatic cancer elicits antitumor immune responses, scientists have tried to stimulate the antitumor activities of the immune system to fight against pancreatic cancer, but has not reached to an expected result. Pancreatic cancer activates both antitumor immune responses and immunosuppressive mechanisms leading to tumor development and progression. This action is achieved through mobilization and activation of immune suppressive cells (CAFs), tolerogenic DCs, MDSCs, TAMs, Treg cells and cancer cells-derived soluble factors that promote the induction of tolerance through the generation of CD4+αchain of IL-2R (CD25)+forkhead box P3 (Foxp3) subset. In addition, pancreatic cancer cells modulate the immune system and avoid detection by effector immune by production of immune suppressive cytokines (e.g., TGF-β, IL-10, and IL-6), by expressing surface molecules that mediate immune suppression (e.g., vascular endothelial growth factors (VEGFs), Fas ligand (Fas-L), programmed death-1 ligand (PD-L1), indolamine-2, and 3-dioxygenase (IDO). Identification of pancreatic cancer-associated antigens has spurred the development of vaccination-based strategies for treatment. Vaccine therapy relies on the administration of biological preparations that include an antigen that is specifically expressed by malignant cells, boosting the natural ability of the immune system to react against neoplastic cells. Potent vaccines stimulate antigen presentation by dendritic cells, hence driving the expansion of antigen-specific effector and memory T cells. Further, immune modulation and immunosuppressive environment by pancreatic cancer can be overcome by enhancing vaccine efficacy by combinatorial therapy. In this paper, we analyze recent preclinical and clinical efforts towards vaccine therapy for pancreatic cancer designed to target pancreatic cancer-associated antigens and to elicit an antitumor response in vivo.
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