Abstract
Immunotherapy has revolutionized the treatment of many cancer types. However, pancreatic ductal adenocarcinomas (PDACs) exhibit poor responses to immune checkpoint inhibitors with immunotherapy-based trials not generating convincing clinical activity. PDAC tumors often have low infiltration of tumor CD8+ T cells and a highly immunosuppressive microenvironment. These features classify PDAC as immunologically “cold.” However, the presence of tumor T cells is a favorable prognostic feature in PDAC. Intrinsic tumor cell properties govern interactions with the immune system. Alterations in tumor DNA such as genomic instability, high tumor mutation burden, and/or defects in DNA damage repair are associated with responses to both immunotherapy and chemotherapy. Cytotoxic or metabolic stress produced by radiation and/or chemotherapy can act as potent immune triggers and prime immune responses. Damage- or stress-mediated activation of nucleic acid-sensing pathways triggers type I interferon (IFN-I) responses that activate innate immune cells and natural killer cells, promote maturation of dendritic cells, and stimulate adaptive immunity. While PDAC exhibits intrinsic features that have the potential to engage immune cells, particularly following chemotherapy, these immune-sensing mechanisms are ineffective. Understanding where defects in innate immune triggers render the PDAC tumor–immune interface less effective, or how T-cell function is suppressed will help develop more effective treatments and harness the immune system for durable outcomes. This review will focus on the pivotal role played by IFN-I in promoting tumor cell–immune cell cross talk in PDAC. We will discuss how PDAC tumor cells bypass IFN-I signaling pathways and explore how these pathways can be co-opted or re-engaged to enhance the therapeutic outcome.
Highlights
pancreatic ductal adenocarcinomas (PDACs) accounts for more than 90% of pancreatic malignancies and is currently the third leading cause of cancer-related death in Western countries (Luchini et al, 2016; Pishvaian and Brody, 2017; McGuigan et al, 2018)
It is possible that inhibiting TREX1 or ENPP1 function could result in more effective activation of DNA-sensing pathways in specific subsets of PDAC, or following treatment with chemotherapy or radiation
While chemoimmunotherapy shows better overall responses than chemotherapy or immunotherapy alone, this benefit is marginal for most patients
Summary
PDAC accounts for more than 90% of pancreatic malignancies and is currently the third leading cause of cancer-related death in Western countries (Luchini et al, 2016; Pishvaian and Brody, 2017; McGuigan et al, 2018). In PDAC patients, chemotherapy has been shown to stimulate the immune response by increasing T-cell response to tumor-associated antigens (Mandili et al, 2020). Cell-based vaccines alone or combined with chemotherapy and ICI present alternative strategies to achieve tumor-targeted immune stimulation.
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