Abstract B60: Role of inflammatory monocyte mobilization in metastatic pancreatic cancer
Authors: Panni Roheena Z. , Sanford Dominic E. , Belt Brian A. , Nywening Timothy M. , Goedegebuure Peter , Linehan David C. 
Published: October 2015

Introduction: More than half of patients with Pancreatic Cancer (PC) present with metastasis. Our group and others have shown that PC induces cellular changes in the liver long before metastatic spread. These pre-metastatic changes include a significant recruitment of inflammatory monocytes (IM) by the chemokine CCL2 (produced by pre-metastatic liver) and its receptor CCR2 (expressed on IM). Based on our preliminary data, we hypothesized that IM mobilization to the liver is essential for growth of metastatic PC. We therefore optimized our model of metastatic PC to study the role of CCR2 inhibition on growth of metastatic PC.

Methods: We implanted a spontaneously derived murine PC cell line (KCKO) orthotopically in the tail of the pancreas of C57BL/6 (WT) mice. We removed the primary tumor on day 10 and divided the spleen into two hemi-spleens. At this time, mice were injected with luciferase expressing tumor cells in the inferior pole of the spleen which was removed after injection and liver metastases were detected by bioluminescence (BLI).

Results: Mice with established liver metastasis were randomized to treatment with CCR2 antagonist (CCR2i), FOLFIRINOX, CCR2i and FOLFIRINOX combination (CCR2i+FOLFIRINOX), or vehicle. Mice were treated for three weeks and were imaged biweekly in order to quantify tumor burden in the liver. Mice were sacrificed after 3 weeks and gene expression and flow cytometry studies were performed on peripheral blood, bone marrow, and liver. Liver metastases were detected by BLI in 70% of mice after 10 days and 100% of mice after 15 days following splenic injection with luciferase expressing tumor cells. Peripheral blood and liver inflammatory monocytes/macrophages were significantly increased in mice bearing liver metastasis. However, CCR2i efficiently blocked the recruitment of inflammatory monocyte/macrophage populations in the liver (p&lt;0.01). Additionally mice treated with CCR2i alone and CCR2i and FOLFIRINOX combination exhibited a shift in the immune gene profile in metastatic liver from a pro-tumor (Type 2) to an anti-tumor (Type 1) immune response. Consequently, metastatic tumor burden was significantly decreased after treatment with CCR2i and FOLFIRINOX. Interestingly, the lowest tumor burden was found in livers of mice treated with combination of CCR2 inhibitor and FOLFIRINOX. This suggests that targeting CCR2 can decrease the growth of liver metastasis in PC.

Conclusion: Our murine model of PC metastasis formation recapitulates the human form of the disease. We demonstrate that inflammatory monocyte recruitment to the liver is important in promoting the development of metastasis in liver. CCR2 blockade in combination with FOLFIRINOX decreases macrophages in the liver and impairs growth of liver metastasis.

Citation Format: Roheena Z. Panni, Dominic E. Sanford, Brian A. Belt, Timothy M. Nywening, Peter Goedegebuure, David C. Linehan. Role of inflammatory monocyte mobilization in metastatic pancreatic cancer. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Innovations in Research and Treatment; May 18-21, 2014; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2015;75(13 Suppl):Abstract nr B60.