Abstract
Simple SummaryPancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer with a dismal prognosis. While immunotherapy has been deemed a breakthrough treatment for various subtypes of cancer, its efficacy in PDAC is limited. This review discusses a wide range of immunotherapies, providing a general introduction to their working mechanism as well as current evidence on their clinical efficacy and immune eliciting abilities in PDAC. Utilizing combination (immuno)therapies to generate synergistic anti-tumor effects may provide the key to successful PDAC treatment.Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease with high mortality. The vast majority of patients present with unresectable, advanced stage disease, for whom standard of care chemo(radio)therapy may improve survival by several months. Immunotherapy has led to a fundamental shift in the treatment of several advanced cancers. However, its efficacy in PDAC in terms of clinical benefit is limited, possibly owing to the immunosuppressive, inaccessible tumor microenvironment. Still, various immunotherapies have demonstrated the capacity to initiate local and systemic immune responses, suggesting an immune potentiating effect. In this review, we address PDAC’s immunosuppressive tumor microenvironment and immune evasion methods and discuss a wide range of immunotherapies, including immunomodulators (i.e., immune checkpoint inhibitors, immune stimulatory agonists, cytokines and adjuvants), oncolytic viruses, adoptive cell therapies (i.e., T cells and natural killer cells) and cancer vaccines. We provide a general introduction to their working mechanism as well as evidence of their clinical efficacy and immune potentiating abilities in PDAC. The key to successful implementation of immunotherapy in this disease may rely on exploitation of synergistic effects between treatment combinations. Accordingly, future treatment approaches should aim to incorporate diverse and novel immunotherapeutic strategies coupled with cytotoxic drugs and/or local ablative treatment, targeting a wide array of tumor-induced immune escape mechanisms.
Highlights
Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease, with a dismal five-year overall survival (OS) rate of 6% [1]
On T cells, the inhibitory cytotoxic T-lymphocyte-associated protein (CTLA)-4 receptor competes with co-stimulatory receptor CD28 for the CD80 and CD86 ligands on antigen presenting cells (APCs), for which CTLA-4 has higher affinity [62,63]
Adjuvants bind onto pattern recognition receptors (PRRs), including toll-like receptors (TLRs), stimulator of IFN genes (STING) and NOD-like receptors (NLRs), which are present on epithelial cells and innate immune cells, including dendritic cells (DCs), and initiate immune responses against pathogens or tumor cells in secondary lymphoid organs [119]
Summary
Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease, with a dismal five-year overall survival (OS) rate of 6% [1]. Systemic and local immune responses have been reported in PDAC patients after treatment with immunotherapy, implying they can instigate an anti-tumor effect [9], albeit not potent enough. In this regard, combination with other immunotherapies, chemotherapy and/or local ablation may work synergistically. We provide an overview of currently available immunotherapies and their anti-tumor effects in PDAC in terms of immune activation and survival, with a focus on clinical research from the past decade. Reduced immune recognition is established by its low mutational burden and through downregulation of MHC-I membrane proteins
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