First published February 12, 2019 - More info
Pancreatic ductal adenocarcinoma (PDAC) represents an immune quiescent tumor that is resistant to immune checkpoint inhibitors. Previously, our group has shown that a GM-CSF secreting allogenic pancreatic tumor cell vaccine (GVAX), may prime the tumor microenvironment by inducing intratumoral T-cell infiltration. Here, we show that untreated PDACs express minimal indoleamine-2, 3-dioxygenase (IDO1); however, GVAX therapy induced IDO1 expression on tumor epithelia as well as vaccine-induced tertiary lymphoid aggregates. IDO1 expression plays a role in regulating the polarization of Th1, Th17, and possibly T-regulatory cells in PDAC tumors. IDO1 inhibitor enhanced anti-tumor efficacy of GVAX in a murine model of PDACs. The combination of vaccine and IDO1 inhibitor enhanced intratumoral T-cell infiltration and function, but adding anti-PD-L1 antibody to the combination did not offer further synergy and in fact may have a negative interaction decreasing the number of intratumoral effector T-cells. Additionally, IDO1 inhibitor in the presence of vaccine therapy, did not significantly modulate intratumoral myeloid derived suppressor cells quantitatively, but diminished their suppressive effect on CD8+ proliferation. Our study thus supports the combination of IDO1 inhibitor and vaccine therapy, however, does not support the combination of IDO1 inhibitor and anti-PD-1/PD-L1 antibody for T cell-inflamed tumors such as PDACs treated with vaccine therapy.