title: Immunosuppressive CD14+HLA-DRlo/negmonocytes are elevated in pancreatic cancer and "primed" by tumor-derived exosomes.
abstract: 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= 22) and age-matched controls (n= 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-DRlo/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-DRlo/negmonocytes 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 anin vitromodel, 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.
authors.affiliation: Department of Biochemistry and Molecular Biology, Mayo Clinic , Rochester, MN, USA.
authors.forename: Naureen
authors.initials: N
authors.lastname: Javeed
authors.affiliation: Human Cellular Therapy Laboratory, Division of Transfusion Medicine, Department of Laboratory Medicine and Pathology, Mayo Clinic , Rochester, MN, USA.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Gustafson
authors.affiliation: Department of Biochemistry and Molecular Biology, Mayo Clinic , Rochester, MN, USA.
authors.forename: Shamit K
authors.initials: SK
authors.lastname: Dutta
authors.affiliation: Division of Hematology, Mayo Clinic , Rochester, MN, USA.
authors.forename: Yi
authors.initials: Y
authors.lastname: Lin
authors.affiliation: Department of Health Sciences Research, Mayo Clinic , Rochester, MN, USA.
authors.forename: William R
authors.initials: WR
authors.lastname: Bamlet
authors.affiliation: Department of Health Sciences Research, Mayo Clinic , Rochester, MN, USA.
authors.forename: Ann L
authors.initials: AL
authors.lastname: Oberg
authors.affiliation: Department of Health Sciences Research, Mayo Clinic , Rochester, MN, USA.
authors.forename: Gloria M
authors.initials: GM
authors.lastname: Petersen
authors.affiliation: Division of Gastroenterology and Hepatology, Mayo Clinic , Rochester, MN, USA.
authors.forename: Suresh T
authors.initials: ST
authors.lastname: Chari
authors.affiliation: Human Cellular Therapy Laboratory, Division of Transfusion Medicine, Department of Laboratory Medicine and Pathology, Mayo Clinic , Rochester, MN, USA.
authors.forename: Allan B
authors.initials: AB
authors.lastname: Dietz
authors.affiliation: Department of Biochemistry and Molecular Biology, Mayo Clinic , Rochester, MN, USA.
authors.forename: Debabrata
authors.initials: D
authors.lastname: Mukhopadhyay
keywords: Exosomes; HLA-DR; immune profiling; immunosuppression; monocytes; pancreatic cancer