Immunosuppressive CD14⁺HLA-DR^lo/neg monocytes are elevated in pancreatic cancer and “primed” by tumor-derived exosomes

Immunological strategies to treat pancreatic cancer offer new therapeutic approaches to improve patient outcomes. Understanding alterations in the immune systems of pancreatic cancer patients will likely lead to advances in immunotherapy for the disease. We profiled peripheral blood leukocytes from pancreatic cancer patients (n D 22) and age-matched controls (n D 20) using flow cytometry. Immune profiling of pancreatic cancer patients identified phenotypic changes in various immune cell populations, including a population of immunosuppressive monocytes (CD14⁺HLA-DR^lo/neg), which were shown to be increased in these patients. There was a correlation between the levels of CD14⁺ monocytes and the levels of CD14⁺HLA-DR^lo/neg monocytes in peripheral blood from pancreatic cancer patients. HLA-DR downregulation of monocytes was shown to occur through pancreatic cancer-derived exosome interactions with monocytes. In an in vitro model, exosomes from patient-derived xenograft cell lines and patient plasma decreased HLA-DR expression on CD14⁺ monocytes. Additionally, tumor-derived exosomes caused immune suppression in monocytes through altered STAT3 signaling, induction of arginase expression, and reactive oxygen species. These findings provide novel insights into the mechanisms that govern immunosuppression in pancreatic cancer. Understanding monocyte-exosome interactions could lead to novel immunotherapies for this disease.