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Abstract

PURPOSE:

Local tumor growth is a major cause of morbidity and mortality in nearly 30% of patients with pancreatic ductal adenocarcinoma (PDAC). Radiotherapy is commonly used for local disease control in PDAC, but its efficacy is limited. We studied the impact of selectively intervening on radiotherapy-induced inflammation as an approach to overcome resistance to radiotherapy in PDAC.

EXPERIMENTAL DESIGN:

PDAC cell lines derived from primary pancreatic tumors arising spontaneously in KrasLSL-G12D/+;Trp53LSL-R172H/+;Pdx-1 Cre mice were implanted into syngeneic mice and tumors were focally irradiated using the Small Animal Radiation Research Platform (SARRP). We determined the impact of depleting T cells and Ly6C+ monocytes as well as inhibiting the chemokine CCL2 on radiotherapy efficacy. Tumors were analyzed by flow cytometry and IHC to detect changes in leukocyte infiltration, tumor viability, and vascularity. Assays were performed on tumor tissues to detect cytokines and gene expression.

RESULTS:

Ablative radiotherapy alone had minimal impact on PDAC growth but led to a significant increase in CCL2 production by tumor cells and recruitment of Ly6C+CCR2+ monocytes. A neutralizing anti-CCL2 antibody selectively inhibited radiotherapy-dependent recruitment of monocytes/macrophages and delayed tumor growth but only in combination with radiotherapy (P < 0.001). This antitumor effect was associated with decreased tumor proliferation and vascularity. Genetic deletion of CCL2 in PDAC cells also improved radiotherapy efficacy.

CONCLUSIONS:

PDAC responds to radiotherapy by producing CCL2, which recruits Ly6C+CCR2+ monocytes to support tumor proliferation and neovascularization after radiotherapy. Disrupting the CCL2-CCR2 axis in combination with radiotherapy holds promise for improving radiotherapy efficacy in PDAC.
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Translational Relevance

Pancreatic ductal adenocarcinoma (PDAC) has demonstrated substantial resistance to radiotherapy. Here, we report that PDAC responds to radiotherapy by releasing inflammatory molecules, including the chemokine CCL2. By recruiting inflammatory monocytes/macrophages to the tumor microenvironment to promote tumor proliferation and vascularization, tumor-derived CCL2 inhibited the efficacy of ablative radiotherapy in a mouse model of PDAC. In contrast, selective blockade of CCL2 using neutralizing antibodies blocked monocyte/macrophage recruitment to tumors and, in combination with radiotherapy, produced antitumor activity with enhanced survival. As primary tumor growth in PDAC is responsible for up to 30% of patient mortality, our findings highlight a potential role for targeting the inflammatory response to radiotherapy for improving local control and patient outcomes.​

​Author information

Kalbasi A1,2, Komar C1,3, Tooker GM1,3, Liu M1,3, Lee JW1,3, Gladney WL1,3, Ben-Josef E1,2, Beatty GL4,3.

1Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania.
2Department of Radiation Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
3Division of Hematology-Oncology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
4Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania. gregory.beatty@uphs.upenn.edu.