Editors' ChoiceCancer

Educating macrophages to clean up the tumor space

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Science Signaling  19 Apr 2016:
Vol. 9, Issue 424, pp. ec91
DOI: 10.1126/scisignal.aaf8930

Tumor-associated macrophages (TAMs) promote cancer fibrosis, which limits drug accessibility to the tumor, by secreting factors that activate fibroblast-mediated extracellular matrix remodeling. Pancreatic ductal adenocarcinoma (PDAC), an aggressive and frequently drug-resistant tumor, has extensive fibrosis and a high number of infiltrating TAMs. TAMs originate from peripheral blood monocytes, cells that control both the formation and resolution of fibrosis in nonmalignant contexts. CD40 is a member of the tumor necrosis factor (TNF) receptor family, present on antigen-presenting cells, and immunotherapy with a CD40 agonist induces the breakdown of fibrotic lesions and the regression of tumors in mice and patients with PDAC. Long et al. uncovered the mechanism underlying the antifibrotic properties of CD40 therapy. Tracking monocyte migration in the peripheral blood of mice engineered to develop PDAC (KPC mice) revealed that injecting mice with an agonist CD40 antibody caused inflammatory monocyte–derived macrophages with abundant CCR2 (a chemokine receptor that defines these cells as “classic” macrophages) to rapidly infiltrate PDAC tumors. However, depleting the alternate subpopulation of monocytes that give rise to resident macrophages prevented this effect. Treating KPC mice or PDAC patients with the CD40 agonist increased the amount of CCL2 (the CCR2 ligand), interferon-γ (IFN-γ), and interleukin-12 in the circulation. Neutralizing CCL2 prevented the infiltration of inflammatory macrophages into tumors in KPC mice in response to CD40 agonist. In both control mice lacking tumors and KPC mice, IFN-γ–induced signaling in inflammatory monocytes was increased by treatment with the CD40 agonist, and neutralizing IFN-γ prevented inflammatory monocytes from breaking down extracellular matrix within tumors in KPC mice. The decrease in type I collagen and fibronectin suggested that matrix metalloproteases (MMPs) were involved. Gene expression analysis of whole-tumor lysates revealed an increase in multiple MMP-encoding genes in response to treatment with the CD40 agonist, but only an increase in MMP13 depended on the presence of inflammatory macrophages and stimulation with IFN-γ. Selective inhibitors of MMP13 prevented the antifibrotic effects of the CD40 agonist. Thus, the combined effects of CCL2- and IFN-γ–dependent macrophage trafficking and programming, respectively, underlie the antifibrotic effects of CD40 agonists. In a manner dependent on inflammatory macrophages, IFN-γ, and MMP13, treating KPC mice with the CD40 agonist improved the efficacy of a chemotherapeutic (gemcitabine) delivered 5 days after delivery of the CD40 agonist. The findings indicate that immunotherapy harnessing macrophage plasticity may be beneficial in pancreatic cancer patients.

K. B. Long, W. L. Gladney, G. M. Tooker, K. Graham, J. A. Fraietta, G. L. Beatty, IFN-γ and CCL2 cooperate to redirect tumor-infiltrating monocytes to degrade fibrosis and enhance chemotherapy efficacy in pancreatic carcinoma. Cancer Discov. 6, 400–413 (2016). [PubMed]

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