Oncotarget

Research Papers:

Peritumoral endothelial indoleamine 2, 3-dioxygenase expression is an early independent marker of disease relapse in colorectal cancer and is influenced by DNA mismatch repair profile

Annabel Meireson, Inès Chevolet, Eva Hulstaert, Liesbeth Ferdinande, Piet Ost, Karen Geboes, Marc De Man, Dirk Van de Putte, Laurine Verset, Vibeke Kruse, Pieter Demetter and Lieve Brochez _

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Oncotarget. 2018; 9:25216-25224. https://doi.org/10.18632/oncotarget.25393

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Abstract

Annabel Meireson1, Inès Chevolet1, Eva Hulstaert1, Liesbeth Ferdinande2, Piet Ost3,8,9, Karen Geboes4, Marc De Man4, Dirk Van de Putte5, Laurine Verset6, Vibeke Kruse7,8, Pieter Demetter6 and Lieve Brochez1,8,9

1Department of Dermatology, Ghent University Hospital, Ghent, Belgium

2Department of Pathology, Ghent University Hospital, Ghent, Belgium

3Department of Radiation-Oncology and Experimental Cancer Research, Ghent University Hospital, Ghent, Belgium

4Department of Gastroenterology and Digestive Oncology, Ghent University Hospital, Ghent, Belgium

5Department of Gastrointestinal Surgery, Ghent University Hospital, Ghent, Belgium

6Department of Pathology, Erasme Hospital, ULB, Brussels, Belgium

7Department of Medical Oncology, Ghent University Hospital, Ghent, Belgium

8Immuno-Oncology Network Ghent (ION Ghent), Ghent, Belgium

9Cancer Research Institute Ghent (CRIG), Ghent, Belgium

Correspondence to:

Lieve Brochez, email: Lieve.Brochez@ugent.be

Keywords: indoleamine 2,3-dioxygenase; colorectal cancer; immune checkpoints; microsatellite instability; MSI

Received: December 05, 2017     Accepted: April 28, 2018     Published: May 18, 2018

ABSTRACT

Targeting immune checkpoint molecules has become a major new strategy in the treatment of several cancers. Indoleamine 2,3-dioxygenase (IDO)-inhibitors are a potential next-generation immunotherapy, currently investigated in multiple phase I-III trials. IDO is an intracellular immunosuppressive enzyme and its expression/activity has been associated with worse prognosis in several cancers.

The aim of this study was to investigate the expression pattern of IDO in colorectal cancer (CRC). In a cohort of 94 CRC patients, primary tumors (PTs) with corresponding tumor-draining lymph nodes (TDLNs, n = 93) and extranodal/distant metastases (n = 27) were retrospectively analyzed by immunohistochemical staining for IDO, CD8 and Foxp3. 45 MSS and 37 MSI-H tumors were selected to compare IDO expression, as these tumors are considered to have different immunogenicity.

A highly consistent expression pattern of IDO was observed in the PT, TDLNs and metastases, indicating that immune resistance may be determined very early in the disease course. IDO was expressed both by tumoral cells and host endothelial cells and these expressions were highly correlated (p < 0.001). IDO expression was observed more frequently in the MSI-H subset compared with the MSS subset (43% vs 22% for tumoral expression (p = 0.042) and 38% vs 16% for endothelial expression (p = 0.021)). Endothelial IDO expression was demonstrated to be a negative prognostic marker for recurrence free survival independent of disease stage and DNA mismatch repair (MMR) status (HR 20.67, 95% CI: 3.05–139.94; p = 0.002). These findings indicate that endothelial IDO expression in primary CRC, in addition to the MMR profile, may be helpful in disease stratification.


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