IDO1 inhibition potentiates vaccine-induced immunity against pancreatic adenocarcinoma
Alex B. Blair, … , Victoria Kim, Lei Zheng
Alex B. Blair, … , Victoria Kim, Lei Zheng
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 8

T cell suppression function of MDSCs was diminished by IDO1 inhibitor through reducing production of the MDSC suppressive factors.

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T cell suppression function of MDSCs was diminished by IDO1 inhibitor th...
Stroma of representative FFPE tumor sections from patients treated with GVAX were microdissected by a pathologist. RNA was purified and amplified, and RNA sequencing was performed. Read count was normalized to the total prior to analysis. IDO1hi and IDO1lo expression was determined by normalized stromal IDO1 expression for comparative analysis of (A) ARG1 and (B) NOS2 gene expression (n = 19). Mice underwent hemispleen procedure receiving 2 × 106 Panc02 PDAC cells followed by administration of 100 mg/kg Cy on day 3 and GVAX on day 4. IDO1 inhibitor (200 μg/kg) was administered by oral gavage twice a day starting on day 3 and continuing for 13 days. Anti–PD-1 antibody (100 μg) or IgG control (100 μg) was given intraperitoneally starting on day 5 and continuing twice a week. At day 13, mice were sacrificed and MDSCs were isolated and used for (C) colorimetric arginase assay or (D) T cell suppression assay via coculture experiment in which MDSCs were cocultured for 48 hours with wild-type CD8+ cells stained with CFSE. Flow cytometry diffusion analysis was performed to assess suppressive ability of treated MDSCs. The percentage of CD8+ T cells that divided at least once were calculated based on fluorescence diffusion. Data represent mean ± SEM of one representative experiment of 5 mice per treatment group pooled and analyzed in triplicate, repeated once. *P < 0.05, **P < 0.01, by unpaired t test and 1-way ANOVA.