Constitutive IDO1 Expression in Human Tumors Is Driven by Cyclooxygenase-2 and Mediates Intrinsic Immune Resistance.

Marc Hennequart,Luc Pilotte,Delia Hoffmann,Etienne De Plaen,Benoît J. Van den Eynde,Vincent Stroobant,Stefania Cane

doi:10.1158/2326-6066.cir-16-0400

Abstract

Tumors use various mechanisms to avoid immune destruction. Cyclooxygenase-2 (COX-2) expression may be a driver of immune suppression in melanoma, but the mechanisms involved remain elusive. Here, we show that COX-2 expression drives constitutive expression of indoleamine 2,3-dioxygenase 1 (IDO1) in human tumor cells. IDO1 is an immunosuppressive enzyme that degrades tryptophan. In a series of seven human tumor lines, constitutive IDO1 expression depends on COX-2 and prostaglandin E2 (PGE2), which, upon autocrine signaling through the EP receptor, activates IDO1 via the PKC and PI3K pathways. COX-2 expression itself depends on the MAPK pathway, which therefore indirectly controls IDO1 expression. Most of these tumors carry PI3K or MAPK oncogenic mutations, which may favor constitutive IDO1 expression. Celecoxib treatment promoted immune rejection of IDO1-expressing human tumor xenografts in immunodeficient mice reconstituted with human allogeneic lymphocytes. This effect was associated with a reduced expression of IDO1 in those ovarian SKOV3 tumors and an increased infiltration of CD3+ and CD8+ cells. Our results highlight the role of COX-2 in constitutive IDO1 expression by human tumors and substantiate the use of COX-2 inhibitors to improve the efficacy of cancer immunotherapy, by reducing constitutive IDO1 expression, which contributes to the lack of T-cell infiltration in "cold" tumors, which fail to respond to immunotherapy. Cancer Immunol Res; 5(8); 695-709. ©2017 AACR.

Highlights

Clinical results from cancer therapy based on the stimulation of antitumor immune responses has introduced a paradigm shift in oncology
Autocrine prostaglandin E2 (PGE2) drives IDO1 expression in human melanoma We selected a series of human cancer cell lines that constitutively express IDO1 and, degrade tryptophan and produce kynurenine in equimolar amounts [13] (Supplementary Table S1)
These results indicated that constitutive IDO1 expression was not triggered by the IFNg signaling pathway in these melanoma cells

Summary

Introduction

Clinical results from cancer therapy based on the stimulation of antitumor immune responses has introduced a paradigm shift in oncology. By releasing brakes that repress T lymphocytes, antibodies able to block inhibitory receptors CTLA-4 or PD1 expressed at the surface of T cells can unleash antitumor immunity, inducing durable tumor responses and improving survival of advanced cancer patients [1]. This favorable outcome is observed in only 20% to 40% of patients. Tumors appear to establish an immunosuppressive microenvironment that prevents the action of antitumor T lymphocytes. Further progress depends on our ability to understand and target these immunosuppressive mechanisms, which are likely manifold and involve a variety of cellular and molecular pathways.

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Conclusion