Kemp SB, Carpenter ES, Steele NG, Donahue KL, Nwosu ZC, Pacheco A, Velez-Delgado A, Menjivar RE, Lima F, The S, Espinoza CE, Brown K, Long D, Lyssiotis CA, Rao A, Zhang Y, Pasca di Magliano M, and Crawford HC. Apolipoprotein E promotes immune suppression in pancreatic cancer through NF-kB-mediated production of CXCL1. Cancer Res 2021.
Pancreatic ductal adenocarcinoma (PDA) is a lethal malignancy with few effective therapeutic options. PDA is characterized by an extensive fibroinflammatory stroma that includes abundant infiltrating immune cells. Tumor-associated macrophages (TAM) are prevalent within the stroma and are key drivers of immunosuppression. TAMs in human and murine PDA are characterized by elevated expression of apolipoprotein E (ApoE), an apolipoprotein that mediates cholesterol metabolism and has known roles in cardiovascular and Alzheimer's disease but no known role in PDA. We report here that ApoE is also elevated in peripheral blood monocytes in PDA patients, and plasma ApoE protein levels stratify patient survival. Orthotopic implantation of mouse PDA cells into syngeneic wild-type or in ApoE-/- mice showed reduced tumor growth in ApoE-/- mice. Histological and mass cytometric (CyTOF) analysis of these tumors showed an increase in CD8+ T cells in tumors in ApoE-/- mice. Mechanistically, ApoE induced pancreatic tumor cell expression of Cxcl1 and Cxcl5, known immunosuppressive factors, through LDL receptor and NF-kB signaling. Taken together, this study reveals a novel immunosuppressive role of ApoE in the PDA microenvironment.
ePub ahead of print
Available for download on Sunday, May 29, 2022