Fig. 1.

CD40 agonists can mediate both T-cell-independent and T-cell-dependent immune mechanisms of tumor regression in pancreatic cancer. The former mechanism involves systemic activation of macrophages that infiltrate the tumor, become tumoricidal, and facilitate the depletion of tumor stroma. In combination with chemotherapy, CD40 agonists can also activate T-cell immunity and mediate major tumor regression; however, anti-tumor T-cell responses can be inhibited by suppressive elements in the tumor microenvironment. A scientific priority going forward is to understand whether blockade of these inhibitory micro-environmental mechanisms will enable adequate priming of an adaptive immune response in concert with CD40 activation in PDA