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Science 331 (6024): 1612-1616

Copyright © 2011 by the American Association for the Advancement of Science

CD40 Agonists Alter Tumor Stroma and Show Efficacy Against Pancreatic Carcinoma in Mice and Humans

Gregory L. Beatty,1,2,6 Elena G. Chiorean,3 Matthew P. Fishman,1 Babak Saboury,5 Ursina R. Teitelbaum,2,6 Weijing Sun,2,6 Richard D. Huhn,4 Wenru Song,4 Dongguang Li,4 Leslie L. Sharp,4 Drew A. Torigian,2,5 Peter J. O’Dwyer,2,6 Robert H. Vonderheide1,2,6,*

Abstract: Immunosuppressive tumor microenvironments can restrain antitumor immunity, particularly in pancreatic ductal adenocarcinoma (PDA). Because CD40 activation can reverse immune suppression and drive antitumor T cell responses, we tested the combination of an agonist CD40 antibody with gemcitabine chemotherapy in a small cohort of patients with surgically incurable PDA and observed tumor regressions in some patients. We reproduced this treatment effect in a genetically engineered mouse model of PDA and found unexpectedly that tumor regression required macrophages but not T cells or gemcitabine. CD40-activated macrophages rapidly infiltrated tumors, became tumoricidal, and facilitated the depletion of tumor stroma. Thus, cancer immune surveillance does not necessarily depend on therapy-induced T cells; rather, our findings demonstrate a CD40-dependent mechanism for targeting tumor stroma in the treatment of cancer.

1 Abramson Family Cancer Research Institute, University of Pennsylvania School of Medicine, 421 Curie Boulevard, Philadelphia, PA 19104, USA.
2 Abramson Cancer Center, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
3 Division of Hematology/Oncology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
4 Pfizer Corporation, New London, CT 06320, USA.
5 Department of Radiology, Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
6 Division of Hematology-Oncology, Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.

* To whom correspondence should be addressed. E-mail: rhv{at}exchange.upenn.edu


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