Статья

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

Gregory L. BeattyAbramson Cancer Center, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USAE. Gabriela ChioreanDivision of Hematology/Oncology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USAMatthew P. FishmanAbramson Family Cancer Research Institute, University of Pennsylvania School of Medicine, 421 Curie Boulevard, Philadelphia, PA 19104, USABabak SabouryDepartment of Radiology, Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USAUrsina TeitelbaumAbramson Cancer Center, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USAWeijing SunAbramson Cancer Center, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USARichard D. HuhnPfizer Corporation, New London, CT 06320, USAWenru SongPfizer Corporation, New London, CT 06320, USADongguang LiPfizer Corporation, New London, CT 06320, USALeslie L. SharpPfizer Corporation, New London, CT 06320, USADrew A. TorigianAbramson Cancer Center, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USAPeter J. O’DwyerAbramson Cancer Center, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USARobert H. VonderheideAbramson Cancer Center, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA

2011en

ABI

Аннотация

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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Идентификаторы

DOI: 10.1126/science.1198443

Цитирования и источники

Цитирований: 2Использованных источников: 0

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