In a pancreatic adenocarcinoma mouse model, a GM-CSF-secreting pancreatic tumor cell vaccine (GVAX) induced CD4+ and CD8+ T cell infiltration, but also induced IDO1 expression on tumor epithelial cells and in lymphoid aggregates, correlating with worse survival. The addition of an IDO1 inhibitor enhanced effector T cell function and survival. Mechanistically, the IDO1 inhibitor led to suppression of Tregs, reduced capacity of MDSCs to suppress T cell proliferation, and Th1 and Th17 polarization of CD4+ T cells. The addition of anti-PD-L1 had no additional effect and may have detracted from the effect of IDO1 inhibitor and GVAX.
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.