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

• Published in: Science (American Association for the Advancement of Science) Vol. 331; no. 6024; pp. 1612 - 1616
• Main 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.
• Format: Journal Article
• Language: English
• Published: Washington, DC American Association for the Advancement of Science 25.03.2011; The American Association for the Advancement of Science
• Subjects: adenocarcinoma; Adult; Aged; Agonists; animal models; Animals; antibodies; Antibodies, Monoclonal - administration & dosage; Antibodies, Monoclonal - adverse effects; Antibodies, Monoclonal - metabolism; Antibodies, Monoclonal - therapeutic use; Antineoplastic agents; Antineoplastic Agents - administration & dosage; Antineoplastic Agents - adverse effects; Antineoplastic Agents - therapeutic use; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Bacteriophages; Biological and medical sciences; Cancer; Carcinoma, Pancreatic Ductal - drug therapy; Carcinoma, Pancreatic Ductal - immunology; Carcinoma, Pancreatic Ductal - pathology; Carcinoma, Pancreatic Ductal - secondary; CD40 Antigens - agonists; CD40 Antigens - immunology; Chemotherapy; Combined treatments (chemotherapy of immunotherapy associated with an other treatment); Deoxycytidine - analogs & derivatives; Deoxycytidine - therapeutic use; Disease Models, Animal; Disease-Free Survival; drug therapy; Effectiveness; Female; Gastroenterology. Liver. Pancreas. Abdomen; Genetic engineering; Human subjects; Humans; Immunity; Immunologic Surveillance; Immunology; immunosuppression; Lesions; Leukocytes; Liver. Biliary tract. Portal circulation. Exocrine pancreas; Lymph nodes; Macrophage Activation; Macrophages; Macrophages - immunology; Male; Medical schools; Medical sciences; Mice; Microenvironments; Middle Aged; monitoring; Monoclonal antibodies; Pancreatic cancer; Pancreatic Neoplasms - drug therapy; Pancreatic Neoplasms - immunology; Pancreatic Neoplasms - pathology; Patients; PDA; Pharmacology. Drug treatments; remission; Rodents; Surveillance; T lymphocytes; T-Lymphocytes - immunology; Tumor Microenvironment; Tumors; Young Adult; Antineoplastic agent; Agonist; Gemcitabine; Cancerology; Immunotherapy; Pancreas cancer; Pyrimidine nucleoside; Pancreatic disease; Human; Antibody; Rodentia; Stroma; Pancreas ductal adenocarcinoma; Malignant tumor; Vertebrata; Chemotherapy; Immunosuppression; Mammalia; Treatment; Antimetabolic; Mouse; Animal; Pyrimidine derivatives; Digestive diseases; Reversibility; Combined treatment; Fluorine Organic compounds; Cancer
• ISSN: 0036-8075; 1095-9203; 1095-9203
• DOI: 10.1126/science.1198443

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 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.