title: CD40 agonists alter tumor stroma and show efficacy against pancreatic carcinoma in mice and humans.
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.
authors: Abramson Family Cancer Research Institute, University of Pennsylvania School of Medicine, 421 Curie Boulevard, Philadelphia, PA 19104, USA.
authors: Gregory L
authors: GL
authors: Beatty
authors: Elena G
authors: EG
authors: Chiorean
authors: Matthew P
authors: MP
authors: Fishman
authors: Babak
authors: B
authors: Saboury
authors: Ursina R
authors: UR
authors: Teitelbaum
authors: Weijing
authors: W
authors: Sun
authors: Richard D
authors: RD
authors: Huhn
authors: Wenru
authors: W
authors: Song
authors: Dongguang
authors: D
authors: Li
authors: Leslie L
authors: LL
authors: Sharp
authors: Drew A
authors: DA
authors: Torigian
authors: Peter J
authors: PJ
authors: O'Dwyer
authors: Robert H
authors: RH
authors: Vonderheide
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000009:adverse effects / Q000378:metabolism / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D019013:CD40 Antigens / Q000819:agonists* / Q000276:immunology*; D021441:Carcinoma, Pancreatic Ductal / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology / Q000556:secondary; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000627:therapeutic use; D004195:Disease Models, Animal; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D007157:Immunologic Surveillance; D008262:Macrophage Activation; D008264:Macrophages / Q000276:immunology; D008297:Male; D051379:Mice; D008875:Middle Aged; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D013601:T-Lymphocytes / Q000276:immunology; D059016:Tumor Microenvironment; D055815:Young Adult; D000093542:Gemcitabine
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D019013:CD40 Antigens; C518149:selicrelumab; D003841:Deoxycytidine; D000093542:Gemcitabine