CD40 agonists alter tumor stroma and show efficacy against pancreatic carcinoma in mice and humans |
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Authors: | Beatty Gregory L Chiorean Elena G Fishman Matthew P Saboury Babak Teitelbaum Ursina R Sun Weijing Huhn Richard D Song Wenru Li Dongguang Sharp Leslie L Torigian Drew A O'Dwyer Peter J Vonderheide Robert H |
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Affiliation: | Abramson Family Cancer Research Institute, University of Pennsylvania School of Medicine, 421 Curie Boulevard, Philadelphia, PA 19104, USA. |
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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. |
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