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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Categories: 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 1

Pancreatic cancer treated with GVAX primes the tumor, upregulating IDO1 and PD-L1 pathway expression.

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Pancreatic cancer treated with GVAX primes the tumor, upregulating IDO1 ...
(A) IHC staining of IDO1 expression in PDACs from patients treated with (n = 21) and without (n = 21) GVAX therapy. (B) Analysis of IDO1 IHC expression of total tumor area in PDACs treated with GVAX compared with untreated tumors, with an identified subset expressing IDO1 highly in the GVAX-treated group. (C) Gene expression of IDO1 measured by microarray was compared between microdissected lymphoid aggregates from 16 tumors grouped according to overall patient survival (OS > 3 years vs. < 1.5 years). (D) IHC staining of IDO1 expression and immune cell infiltration of CD3+, CD4+, and CD8+ cells in PDACs treated with and without GVAX therapy. The same representative sample in A is utilized again here. (E) IHC representations and (F) graphical comparison of IDO1 and PD-L1 lymphoid aggregate expression by IHC following GVAX treatment (n = 16). If IDO1 expression is not upregulated, PD-L1 expression is not detectable. If PD-L1 expression is upregulated, IDO1 expression is upregulated. In some cases, IDO1 expression is increased but PD-L1 expression remains low. *P < 0.05 by unpaired t test. Scale bars, 100 μm.