IDO1 inhibition potentiates vaccine-induced immunity against pancreatic adenocarcinoma
Alex B. Blair, … , Victoria Kim, Lei Zheng
Alex B. Blair, … , Victoria Kim, Lei Zheng
Published April 1, 2019; First published February 12, 2019
Citation Information: J Clin Invest. 2019;129(4):1742-1755. https://doi.org/10.1172/JCI124077.
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Research Article Immunology Oncology

IDO1 inhibition potentiates vaccine-induced immunity against pancreatic adenocarcinoma

Abstract

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 antitumor 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 had 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 supports the combination of IDO1 inhibitor and vaccine therapy; however, it 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.

Authors

Alex B. Blair, Jennifer Kleponis, Dwayne L. Thomas II, Stephen T. Muth, Adrian G. Murphy, Victoria Kim, Lei Zheng

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Figure 3

High IDO1 expression upregulation is associated with a shift to an antitumor immune cell environment.

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High IDO1 expression upregulation is associated with a shift to an antit...
(A) Total number of Tregs (CD4+CD25+Foxp3+) quantified by flow cytometry analysis in tumor-infiltrating lymphocytes of tumor-bearing mice of the Panc02 hemispleen model and indicated treatments. Data represent mean ± SEM from one representative experiment of 4–5 mice per treatment group, repeated twice. Comparisons of the (B) percentage of Th1 (CD45+CD3+CD8–Foxp3–RORgt–Tbet+), (C) Th2 (CD45+CD3+CD8–Foxp3–RORgt–GATA3+), and (D) Th0 (CD45+CD3+CD8–Foxp3–RORgt–Tbet–GATA3–) subsets of cells in IDO1hi and IDO1lo human PDACs treated with GVAX. Comparison of the percentage of (E) Th17+ cells (CD45+CD3+CD8–Foxp3–RORgt+) and (F) Tregs (CD45+CD3+CD8–Foxp3+) in lymphoid aggregates of IDO1hi and IDO1lo PDACs treated with GVAX. (G) Comparison of the cell density of CD8+ cells (CD45+CD3+CD8+) in IDO1hi and IDO1lo PDACs following GVAX treatment (n = 16). Expression was quantified using Image Analysis Software (Aperio). *P < 0.05, **P < 0.01; NS, not significant, by unpaired t test.