Inflammatory Monocyte Mobilization Decreases Patient Survival in Pancreatic Cancer: A Role for Targeting the CCL2/CCR2 Axis

Abstract

Purpose To determine the role of the CCL2/CCR2 axis and inflammatory monocytes (IM; CCR2+/CD14+) as immunotherapeutic targets in the treatment of pancreatic cancer (PC). Experimental Design Survival analysis was performed to determine if the prevalence of pre-operative blood monocytes correlates with survival in PC patients following tumor resection. IM prevalence in the blood and bone marrow of PC patients and controls was compared. The immunosuppressive properties of IM and macrophages in the blood and tumors, respectively, of PC patients were assessed. CCL2 expression by human PC tumors was compared to normal pancreas. A novel CCR2 inhibitor (PF-04136309) was tested in an orthotopic model of murine PC. Results Monocyte prevalence in the peripheral blood correlates inversely with survival, and low monocyte prevalence is an independent predictor of increased survival in PC patients with resected tumors. IM are increased in the blood and decreased in the bone marrow of PC patients compared to controls. An increased ratio of IM in the blood versus the bone marrow is a novel predictor of decreased patient survival following tumor resection. Human PC produces CCL2, and immunosuppressive CCR2+ macrophages infiltrate these tumors. Patients with tumors that exhibit high CCL2 expression/low CD8 T cell infiltrate have significantly decreased survival. In mice, CCR2 blockade depletes IM and macrophages from the primary tumor and premetastatic liver resulting in enhanced anti-tumor immunity, decreased tumor growth, and reduced metastasis. Conclusions IM recruitment is critical to PC progression, and targeting CCR2 may be an effective immunotherapeutic strategy in this disease.

Dynamics of Chemokine, Cytokine, and Growth Factor Serum Levels in BRAF-Mutant Melanoma Patients during BRAF Inhibitor Treatment

“…PD, Progressive disease; PR, partial response; SD, stable disease. migration, and invasion (35,36,(38)(39)(40)(41). Conversely, the current study also found an increase in CCL2 from PRE to EDT correlated with better RECIST response.…”

“…High serum levels of CCL2 are known to correlate with poorer prognosis in breast and pancreatic cancer patients (35,36). Recently Knight et al (37) showed that BRAF-mutant melanoma cell lines have reduced CCL2 mRNA and protein production following treatment with a BRAFi.…”

Chemotherapy of colorectal liver metastases induces a rapid rise in intermediate blood monocytes which predicts treatment response

“…This finding is in line with a proposed pro-tumor function of classical monocytes, as they were recently reported to correlate with poor prognosis of pancreatic cancer patients. 26 In contrast to total intermediate monocytes, the potentially pro-angiogenic TEM subset of intermediate monocytes did not significantly increase in response to chemotherapy. In line, when we previously compared TEM frequency in the blood of CRC patients and healthy individuals, no significant difference was detected.…”

Control of metastatic niche formation by targeting APBA3/Mint3 in inflammatory monocytes

“…Even in metastatic cascades, the CCL2-CCR2 axis is a key pathway for IM recruitment, which in turn promotes tumor colonization and metastasis by secreting VEGFA (14,15). Moreover, the prevalence of IMs in the peripheral blood, as induced by the CCL2-CCR2 axis, correlates with liver metastasis, adverse outcome, and shorter patient survival in pancreatic cancer (16). Although the cellular landscapes involved in metastasis formation have been well-described with macrophage lineages, the molecular mechanisms underlying metastasis (such as with metabolic fueling and metastasis-associated monocytes/macrophages) remain unclear.…”