CD40 agonists drive macrophage anti-tumour functions, and induce systemic immune activation and improved survival in an orthotopic model of pancreatic cancer
Pancreatic cancer represents an area of high unmet medical need. Antibodies agonising CD40 (αCD40) inhibit tumor growth in preclinical models, and are showing activity in early clinical trials in pancreatic cancer. αCD40 antibodies can directly drive apoptosis and promote antibody-dependent cell cytotoxicity of CD40 positive tumor cells, and may also drive antitumor effects through endothelial cells and B cells. However, data from preclinical models indicate that a major mechanism of action for αCD40 antibodies is through targeting of macrophages and dendritic cells, in some cases promoting long term CD8 T cell-dependent anti-tumor immunity. Pancreatic tumors often become highly infiltrated with immunosuppressive tumor macrophages.
Our aim was therefore to test the hypothesis that αCD40 inhibits pancreatic tumor growth and spread by re-educating tumor macrophages to have anti-tumor functions, promoting a Th1 anti-tumor immune response, and gaining direct tumoricidal activity.
We found that CD40 activation licenses human macrophage anti-tumor functions in vitro, and that this was dependent on the presence of T cell derived cytokines. In a syngeneic orthotopic model of pancreatic cancer (Pan02), we found that αCD40 significantly improved survival. This correlated with a significant enhancement in macrophage activation and in systemic immune activation (reduction in myeloid derived suppressor cells and increase in CD8 T cells).
These data add support to the hypothesis that αCD40 inhibits pancreatic tumor growth through promoting anti-tumor functions of tumor macrophages.