Activation of the Kynurenine Pathway in Human Malignancies Can Be Suppressed by the Cyclin-Dependent Kinase Inhibitor Dinaciclib.

Christin Riess,Christian Junghanss,Claudia Maletzki,Annette Zimpfer,Julia Gesche,Daniel Strüder,Nina Irmscher,Björn Schneider,Grazyna Domanska,Fatemeh Shokraie,Hanna Kehnscherper,Carl Friedrich Classen,Elisa Wirthgen

doi:10.3389/fimmu.2020.00055

Christin Riess, Christian Junghanss + Show 11 more

Open Access

https://doi.org/10.3389/fimmu.2020.00055

Copy DOI

Abstract

Indoleamine 2,3-dioxygenase (IDO) and tryptophan 2,3-dioxygenase (TDO2) are the key enzymes of tryptophan (TRP) metabolism in the kynurenine pathway (KP). Both enzymes function as indicators of immunosuppression and poor survival in cancer patients. Direct or indirect targeting of either of these substances seems thus reasonable to improve therapy options for patients. In this study, glioblastoma multiforme (GBM) as well as head and neck squamous cell carcinomas (HNSCC) were examined because of their different mechanisms of spontaneous and treatment-induced immune escape. Effects on gene expression and protein levels were examined. Accompanying assessment of TRP metabolites from treated GBM cell culture supernatants was conducted. Our results show a heterogeneous and inversely correlated expression profile of TRP-metabolizing genes among GBM and HNSCC cells, with low, but inducible IDO1 expression upon IFNγ treatment. TDO2 expression was higher in GBM cells, while genes encoding kynurenine aminotransferases were mainly confined to HNSCC cells. These data indicate that the KP is active in both entities, with however different enzymes involved in TRP catabolism. Upon treatment with Temozolomide, the standard of care for GBM patients, IDO1 was upregulated. Comparable, although less pronounced effects were seen in HNSCC upon Cetuximab and conventional drugs (i.e., 5-fluorouracil, Gemcitabine). Here, IDO1 and additional genes of the KP (KYAT1, KYAT2, and KMO) were induced. Vice versa, the novel yet experimental cyclin-dependent kinase inhibitor Dinaciclib suppressed KP in both entities. Our comprehensive data imply inhibition of the TRP catabolism by Dinaciclib, while conventional chemotherapeutics tend to activate this pathway. These data point to limitations of conventional therapy and highlight the potential of targeted therapies to interfere with the cells' metabolism more than anticipated.

Highlights

Tumor cells release immunosuppressive factors that shape a tolerogenic environment and enable progression and invasion
We focused on the expression of indoleamine 2 (IDO1) and IDO-related kynurenine pathway (KP) genes and their potential involvement in immune evasion in experimental models of head and neck squamous cell carcinomas (HNSCC) and glioblastoma multiforme (GBM)
We were able to show that the KP is active in both entities, with different enzymes involved in TRP catabolism

Summary

Introduction

Tumor cells release immunosuppressive factors that shape a tolerogenic environment and enable progression and invasion. IDO1 activity inhibits T-cell activation and proliferation and even mediates regulatory T-cell recruitment to the tumor microenvironment, provoking local immune tolerance. In head and neck squamous cell carcinomas (HNSCCs), IDO1 inversely correlates with programmed cell death protein ligand 1, which constitutes an important prognostic biomarker for immune-checkpoint inhibition [11]. The increased IDO1 activation decreases intratumoral TRP levels, resulting in tumor starvation and increase in kynurenine (KYN) metabolites (which are toxic to lymphocytes) [12]. This immune exhaustion may be further boosted by conventional chemotherapeutics, leading to decreased efficacy. IDO1 overexpression in the tumor microenvironment intimately impairs patients’ outcome and may serve as a future prognostic predictor and drug target [13,14,15,16,17,18]

Methods

Results

Conclusion