CD40 agonists alter tumor stroma and show efficacy against pancreatic carcinoma in mice and humans
Gregory L Beatty, Elena G Chiorean, Matthew P Fishman, Babak Saboury, Ursina R Teitelbaum, Weijing Sun, Richard D Huhn, Wenru Song, Dongguang Li, Leslie L Sharp, Drew A Torigian, Peter J O'Dwyer, Robert H Vonderheide, Gregory L Beatty, Elena G Chiorean, Matthew P Fishman, Babak Saboury, Ursina R Teitelbaum, Weijing Sun, Richard D Huhn, Wenru Song, Dongguang Li, Leslie L Sharp, Drew A Torigian, Peter J O'Dwyer, Robert H Vonderheide
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.
Trial registration: ClinicalTrials.gov NCT00711191.
Figures
Source: PubMed