2832 - Apolipoprotein E Mediates Radioresistance of Pancreatic Adenocarcinoma

T. Laufer¹, V. Gandhi², and A. C. Mueller³; ¹Department of Radiation Oncology, Sidney Kimmel Medical College of Thomas Jefferson University, Philadelphia, PA, ²Department of Radiation Oncology, Sidney Kimmel Medical College & Cancer Center at Thomas Jefferson University, Philadelphia, PA, ³Department of Radiation Oncology, Sidney Kimmel Medical College & Cancer Center at Thomas Jefferson University, Philadelpha, PA

Purpose/Objective(s): Pancreatic ductal adenocarcinoma (PDAC) is a uniformly aggressive malignancy and is the fourth-highest cause of cancer-related deaths in the United States. Despite major advances in technological capabilities that have improved radiotherapy outcomes and toxicity profiles across diseases, success treating PDAC with RT remains limited. This resistance is increasingly understood to be mediated in part by the PDAC tumor microenvironment (TME) of desmoplastic stroma characterized by suppressive polarization of immune cells and an anti-inflammatory setting.

The lipid transporter Apolipoprotein E is secreted by macrophages in response to lipids in the vascular endothelium where it incorporates into cholesterol particles and promotes M2 polarization, preventing inflammation and atherosclerotic plaque rupture. This key athero-protective mediator of cholesterol clearance was recently implicated in immunosuppression within the PDAC TME. ApoE secretion by tumor-associated macrophages (TAMs) in response to lipid accumulation in the PDAC TME can drive polarization of macrophages to the anti-inflammatory, “alternatively activated” phenotype, thus suppressing immune activity and promoting tumor growth.

We observed that ApoE is significantly increased following radiation in both mouse models and patient samples.

We hypothesize that ApoE secretion after radiation contributes to radioresistance of pancreatic cancer by promoting and immunosuppressive TME. We further hypothesize that blockade of ApoE activity in TAMs can mitigate ApoE-mediated immunosuppression and allow for increased anti-tumor effect of radiation. Materials/

Methods: We used a heterotopic syngeneic murine tumor model to assess differential radiosensitivity in the setting of ApoE loss. PK5L1940 KPC cells were injected into the flanks of wildtype C57BL/6 mice and homozygous ApoE^-/- mice on the C57BL/6 background. Mice were then treated with a single fraction of tumor-directed RT to 16 Gy and tumor size was measured monitored twice weekly.

Results: We have found that ApoE expression is upregulated following radiation therapy in mouse tumors and following neoadjuvant chemo and radiation therapy in PDAC patients. Tumors in the ApoE^-/- mice demonstrated significantly slower growth kinetics following RT compared to the WT mice. These mice also survived longer compared to controls.

Conclusion: ApoE is a mediator of PDAC resistance to radiation. Inhibition of ApoE activity in the PDAC TME is a potential strategy for improving local control following radiotherapy for PDAC patients.