American Association for Cancer Research
21598290cd151032-sup-154697_2_supp_3362314_b2nwkn.pdf (47 kB)

Supplementary Methods from IFNγ and CCL2 Cooperate to Redirect Tumor-Infiltrating Monocytes to Degrade Fibrosis and Enhance Chemotherapy Efficacy in Pancreatic Carcinoma

Download (47 kB)
journal contribution
posted on 2023-04-03, 21:00 authored by Kristen B. Long, Whitney L. Gladney, Graham M. Tooker, Kathleen Graham, Joseph A. Fraietta, Gregory L. Beatty

Supplementary Methods




Molecular Pathology and Imaging Cores of the Penn Center

W. W. Smith Charitable Trust

Department of Defense

Damon Runyon Cancer Research Foundation

Doris Duke Charitable Foundation



Dense fibrosis and a robust macrophage infiltrate are key therapeutic barriers in pancreatic ductal adenocarcinoma (PDAC). CD40 activation can circumvent these barriers by inducing macrophages, originating from peripheral blood monocytes, to deplete fibrosis. The precise mechanism and therapeutic implications of this antifibrotic activity, though, remain unclear. Here, we report that IFNγ and CCL2 released systemically in response to a CD40 agonist cooperate to redirect a subset of Ly6C+CCR2+ monocytes/macrophages to infiltrate tumors and deplete fibrosis. Whereas CCL2 is required for Ly6C+ monocyte/macrophage infiltration, IFNγ is necessary for tumor-infiltrating monocytes/macrophages to shift the profile of matrix metalloproteinases (MMP) in tumors, leading to MMP-dependent fibrosis degradation. In addition, MMP13-dependent loss of extracellular matrix components induced by a CD40 agonist increased PDAC sensitivity to chemotherapy. Our findings demonstrate that fibrosis in PDAC is a bidirectional process that can be rapidly altered by manipulating a subset of tumor-infiltrating monocytes, leading to enhanced chemotherapy efficacy.Significance: We report that CD40 agonists improve chemotherapy efficacy in pancreatic carcinoma by redirecting tumor-infiltrating monocytes/macrophages to induce fibrosis degradation that is dependent on MMPs. These findings provide novel insight into the plasticity of monocytes/macrophages in cancer and their capacity to regulate fibrosis and modulate chemotherapy efficacy in pancreatic carcinoma. Cancer Discov; 6(4); 400–13. ©2016 AACR.This article is highlighted in the In This Issue feature, p. 331

Usage metrics

    Cancer Discovery



    Ref. manager