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The microenvironment that surrounds pancreatic ductal adenocarcinoma (PDAC) is profoundly desmoplastic and immunosuppressive. Understanding triggers of immunosuppression during the process of pancreatic tumorigenesis would aid in establishing targets for effective prevention and therapy. Here, we interrogated differential molecular mechanisms dependent on cell of origin and subtype that promote immunosuppression during PDAC initiation and in established tumors. Transcriptomic analysis of cell-of-origin-dependent epithelial gene signatures revealed that Nt5e/CD73, a cell-surface enzyme required for extracellular adenosine generation, is one of the top 10% of genes overexpressed in murine tumors arising from the ductal pancreatic epithelium as opposed to those rising from acinar cells. These findings were confirmed by IHC and high-performance liquid chromatography. Analysis in human PDAC subtypes indicated that high Nt5e in murine ductal PDAC models overlaps with high NT5E in human PDAC squamous and basal subtypes, considered to have the highest immunosuppression and worst prognosis. Multiplex immunofluorescent analysis showed that activated CD8+ T cells in the PDAC tumor microenvironment express high levels of CD73, indicating an opportunity for immunotherapeutic targeting. Delivery of CD73 small-molecule inhibitors through various delivery routes reduced tumor development and growth in genetically engineered and syngeneic mouse models. In addition, the adenosine receptor Adora2b was a determinant of adenosine-mediated immunosuppression in PDAC. These findings highlight a molecular trigger of the immunosuppressive PDAC microenvironment elevated in the ductal cell of origin, linking biology with subtype classification, critical components for PDAC immunoprevention and personalized approaches for immunotherapeutic intervention.SignificanceDuctal-derived pancreatic tumors have elevated epithelial and CD8+GZM+ T-cell CD73 expression that confers sensitivity to small-molecule inhibition of CD73 or Adora2b to promote CD8+ T-cell-mediated tumor regression. See related commentary by DelGiorno, p. 977.

Although thrombocytopenia is common in end-stage liver disease, severe, refractory thrombocytopenia during liver transplantation is rare, and if immune based, usually presents months or years later. This case describes an adult woman in whom preoperative evaluation had not determined an immune-related cause of thrombocytopenia. Clot strength was dramatically impaired as measured by thrombelastography during the transplant. Following a lack of response to repeat platelet transfusions, splenectomy was performed after graft reperfusion with rapid temporal restoration of clot strength. This case shows a severe manifestation of perioperative thrombocytopenia during liver transplantation and clinically guided management when measured clot strength is too low for accurate determination. [ABSTRACT FROM AUTHOR]

The article presents a case study of a 38-year-old woman with abdominalgunshot injury who was given oral ciprofloxacin after being treated with endoscopic retrograde cholangiopancreatography (ERCP).

Pancreatic cancer remains a highly lethal malignancy. We have recently shown that simultaneous expression of Kras and mutant Tp53R175H promotes invasive ductal adenocarcinoma from pancreatic ductal cells. We hypothesized specific mutations in TP53 have divergent mechanisms of transforming ductal cells. In order to understand the role of mutant TP53 in transforming pancreatic ductal cells, we used a lentiviral system to express mutant TP53R175H and TP53R273H, two of the most frequently mutated TP53 alleles in pancreatic cancer patients, in immortalized, but not transformed, pancreatic ductal epithelial cells carrying a KRAS mutation (HPNE:KRASG12D). Mutant TP53 expression enhanced colony formation and an RPPA assay results revealed TP53R175H uniquely induced HSP70 expression in HPNE:KRASG12D cells. In the context of TP53R175H expression; we observed nuclear localization of HSP70. We performed immunoprecipitation experiments to show mutant p53R175H binds to HSP70. We also provide evidence mutant p53R175H is important for HSP70 stability and, more importantly, HSP70 is required for mutant p53 stability. These data are critical in the context of events leading to cellular transformation in the pancreas. [ABSTRACT FROM AUTHOR]

Pancreatic cancer remains a highly lethal malignancy. We have recently shown that simultaneous expression of Kras and mutant Tp53 R175H promotes invasive ductal adenocarcinoma from pancreatic ductal cells. We hypothesized specific mutations in TP53 have divergent mechanisms of transforming ductal cells. In order to understand the role of mutant TP53 in transforming pancreatic ductal cells, we used a lentiviral system to express mutant TP53 R175H and TP53 R273H , two of the most frequently mutated TP53 alleles in pancreatic cancer patients, in immortalized, but not transformed, pancreatic ductal epithelial cells carrying a KRAS mutation (HPNE:KRAS G12D ). Mutant TP53 expression enhanced colony formation and an RPPA assay results revealed TP53 R175H uniquely induced HSP70 expression in HPNE:KRAS G12D cells. In the context of TP53 R175H expression; we observed nuclear localization of HSP70. We performed immunoprecipitation experiments to show mutant p53 R175H binds to HSP70. We also provide evidence mutant p53 R175H is important for HSP70 stability and, more importantly, HSP70 is required for mutant p53 stability. These data are critical in the context of events leading to cellular transformation in the pancreas., (Copyright © 2019 Elsevier B.V. All rights reserved.)