![]() ![]() Trained innate immunity is an evolutionarily ancient program of immunological memory that has recently come under in-depth scientific investigation. Therefore, novel therapeutics are desperately needed that can not only specifically target the pancreas, but that can also infiltrate the dense desmoplastic stroma, and that are capable of inciting robust antit-umor immune responses despite the immunosuppressive TME. Together these conditions make it exceptionally challenging to effectively deliver immunotherapies to the pancreas and for these therapeutics to successfully activate anti-tumor immune responses if they do arrive there. PDAC is characterized by a dense pro-tumorigenic desmoplastic stroma, an abundance of immunosuppressive cell subsets within this stroma such as tumor-associated macrophages (TAMs), regulatory T-cells (T-regs), and myeloid-derived suppressor cells (MDSCs), a dearth of activated anti-tumor immune cells, and hypo-vascularity that lends to a hypoxic microenvironment 13, 14, 15, 16. The Phase I and II clinical trials using CTLA-4 and PD-1 inhibitors both alone and in combination have been deemed ineffective for the treatment of PDAC, which is likely explained by the non-immunogenic nature of PDAC 10, 11, 12.Ī major challenge to the successful application of immunotherapy in PDAC is overcoming the immunosuppressive pancreatic tumor microenvironment (TME). Furthermore, pancreatic cancer has shown little responsiveness to immunotherapies which have shown remarkable effects in other solid tumors 5, 6, 7, 8, 9. Even in patients who are eligible for resection, the 5-year survival rate is only 20–25% 4. Pancreatic cancer is particularly lethal due to the fact that in early stages there are seldom clinical symptoms, which results in 75–80% of patients being diagnosed with advanced, non-resectable disease 3, 4. In addition, as the demographics of the United States shift, it is projected that pancreatic cancer will become the second leading cause of cancer-related mortality by 2030 and thus presents a significant future challenge for clinicians 2. Although the survival rate since 2014 has increased from 6 to 10%, pancreatic cancer remains refractory to the majority of currently available therapeutics. The diagnosis of pancreatic ductal adenocarcinoma (PDAC) is a devastating one, with only 10% of patients surviving the past 5 years 1. These findings characterize the dynamic mechanisms and localization of peripheral trained immunity and identify an application of trained immunity to cancer. In orthotopic models of pancreatic ductal adenocarcinoma, β-glucan treated mice show significantly reduced tumor burden and prolonged survival, which is further enhanced when combined with immunotherapy. These cells can be activated upon exposure to tumor cells and tumor-derived factors, and show enhanced cytotoxicity against pancreatic tumor cells. Here we demonstrate that yeast-derived particulate β-glucan, an inducer of trained immunity, traffics to the pancreas, which causes a CCR2-dependent influx of monocytes/macrophages to the pancreas that display features of trained immunity. Innate immune cells are critical to anti-tumor immunosurveillance and recent studies have revealed that these populations possess a form of memory, termed trained innate immunity, which occurs through transcriptomic, epigenetic, and metabolic reprograming. Despite the remarkable success of immunotherapy in many types of cancer, pancreatic ductal adenocarcinoma has yet to benefit. ![]()
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