Apolipoprotein E Promotes Immune Suppression in Pancreatic Cancer through NF-κB–Mediated Production of CXCL1
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Abstract
Abstract Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy with few effective therapeutic options. PDAC 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 PDAC 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 PDAC. We report here that ApoE is also elevated in peripheral blood monocytes in PDAC patients, and plasma ApoE protein levels stratify patient survival. Orthotopic implantation of mouse PDAC cells into syngeneic wild-type or in ApoE−/− mice showed reduced tumor growth in ApoE−/− mice. Histologic 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-κB signaling. Taken together, this study reveals a novel immunosuppressive role of ApoE in the PDAC microenvironment. Significance: This study shows that elevated apolipoprotein E in PDAC mediates immune suppression and high serum apolipoprotein E levels correlate with poor patient survival. See related commentary by Sherman, p. 4186
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ApoE is strikingly elevated in several tumors and associated with poor survival of tumor patients.
“The role of ApoE in cancer is being intensively investigated because ApoE is strikingly elevated in several tumors and associated with poor survival of tumor patients [73, 74].”
From Single-cell transcriptome reveals the reprogramming of immune microenvironment during the transition from MASH to HCC (2025) · cites this paper as [73]
The Introduction reports increased ApoE levels in several tumor types. The Results link high plasma APOE to shorter survival specifically in patients with pancreatic ductal adenocarcinoma (PDAC), not tumor patients generally; they also report no significant overall difference in plasma APOE between PDAC patients and controls. The broader survival claim therefore exceeds what this paper establishes. (LLM, conf=0.87)
Experimental — accuracy not yet measuredOrthotopic implantation in ApoE-deficient mice exhibits less tumor burden, reduced immunosuppression and increased tumor-infiltrating CD8+ T cells.
“Correspondingly, orthotopic implantation in ApoE-deficient mice exhibits less tumor burden, reduced immunosuppression and increased tumor-infiltrating CD8+ T cells [73].”
From Single-cell transcriptome reveals the reprogramming of immune microenvironment during the transition from MASH to HCC (2025) · cites this paper as [73]
Macrophage-derived ApoE promotes tumorigenesis either through inducing the expression of Cxcl1 and Cxcl5 in pancreatic ductal adenocarcinoma cells, or activating PI3K-AKT signaling pathway in recipient gastric cancer cells.
“Macrophage-derived ApoE promotes tumorigenesis either through inducing the expression of Cxcl1 and Cxcl5 in pancreatic ductal adenocarcinoma cells [73], or activating PI3K-AKT signaling pathway in recipient gastric cancer cells [75].”
From Single-cell transcriptome reveals the reprogramming of immune microenvironment during the transition from MASH to HCC (2025) · cites this paper as [73]
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Extrinsic KRAS signaling shapes the pancreatic microenvironment through fibroblast reprogramming
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- Authors
- Kemp, S. B., Carpenter, E. S., Steele, N. G., Donahue, K. L., Nwosu, Z. C., Pacheco, A., Velez-Delgado, A., Menjivar, R. E., Lima, F., The, S., Espinoza, C. E., Brown, K., Long, D., Lyssiotis, C. A., Rao, A., Zhang, Y., Pasca di Magliano, M., & Crawford, H. C.
- Affiliations
- University of Michigan (US)
- 3Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, Michigan.
- Corresponding author
- Crawford, Howard C.
- ORCID
- Venue
- Cancer Research
- Published
- 2021-05-28
- Volume
- 81
- Issue
- 16
- Pages
- 4305-4318
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- PMC
- PMC8445065
- OpenAlex
- W3164787484
- Cited by
- 197
- References
- 50
- Citations by year
- 2026: 37 · 2025: 37 · 2024: 43 · 2023: 55 · 2022: 21 · 2021: 4
- FWCI
- 11.46
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Cancer Research (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- Funders
- National Institutes of Health (U01CA224145, T32-GM113900, T32-DK094775, T32-CA009676, R37CA237421)
- National Cancer Institute (R01CA151588, R01CA198074, F31-CA247076, R37CA214955)
- American Cancer Society (PF-19-096-01, RSG-16-005-01)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
- Health Sciences › Medicine › Oncology › Pancreatic and Hepatic Oncology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
- Keywords
- apolipoprotein E, pancreatic ductal adenocarcinoma, tumor immunosuppression, NF-κB signaling, CXCL1, CXCL5, tumor-associated macrophages, CD8+ T cells, LDL receptor, tumor microenvironment, patient survival, cholesterol metabolism
- MeSH terms
- Mice, Knockout, ApoE, RNA-Seq, Animals, Apolipoproteins E, Fibroblasts, Humans, Immune System, Immunosuppression Therapy, Inflammation, Macrophages, Mice, Inbred C57BL, Pancreatic Neoplasms, Receptors, LDL, Mass Spectrometry, Signal Transduction, NF-kappa B, Treatment Outcome, Cell Line, Tumor, Mice, Chemokine CXCL1, Single-Cell Analysis
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