The immunotherapeutic role of indoleamine 2,3‐dioxygenase in head and neck squamous cell carcinoma: A systematic review

Abstract

Background Novel cancer immunotherapy seeks to harness the body's own immune system and tip the balance in favour of antitumour activity. The intracellular enzyme indoleamine 2,3‐dioxygenase (IDO) is a critical regulator of the tumour microenvironment (TME) via tryptophan metabolism. The potential immunotherapeutic role of IDO in head and neck squamous cell carcinoma (HNSCC) requires further exploration. We aim to assess the evidence on IDO in HNSCC. Methods A systematic review of literature and clinical trials databases. Results We included 40 studies: seven involved cell lines: eight assessed tumour immunohistochemistry: ten measured IDO gene transcription: 15 reported on clinical trials. Increased cell line IDO expression was postulated to adversely affect tumour metabolism and apoptosis. Immunohistochemical IDO expression correlated with worse survival. Gene transcription studies associated IDO with positive PD‐L1 and human papillomavirus (HPV) status. Phase I/II clinical trials showed (a) overall response (34%‐55%) and disease control rates (62%‐70%) for IDO1 inhibitor in combination with a PD‐1 inhibitor, (b) similar safety profiles when both are used in combination therapy compared to each as monotherapies and (c) IDO gene expression as a predictive biomarker for response to PD‐L1 therapy. Conclusions IDO expression is increased in the TME of HNSCC, which correlates with poor prognosis. However, the exact mechanism of IDO‐driven immune modulation in the TME is an enigma. Future translational studies should map IDO activity during HNSCC treatment and elucidate its precise role in the TME, such research will underpin the development of clinical trials establishing the efficacy of IDO inhibitors in HNSCC.

The Role of Indoleamine 2, 3-Dioxygenase 1 in Regulating Tumor Microenvironment

“…Friberget et al first reported the IDO1 pathway as a possible tumor immune escape mechanism in 2002 when they observed IDO1 expression by monocytes in tumor tissues and tumor-draining lymph nodes [ 67 ]. In the past decade, numerous studies have observed high IDO1 levels in human tumors, including glioblastoma, head and neck squamous cell carcinoma, breast cancer adrenocortical carcinoma, esophageal squamous cell carcinoma, gastric cancer, and colon cancer [ 68 , 69 , 70 , 71 , 72 , 73 , 74 , 75 ].…”

Regulation of the Immune Checkpoint Indoleamine 2,3-Dioxygenase Expression by Epstein–Barr Virus

“…They prevent ligand–receptor engagement, avoiding diseases such as autoimmune ones. Its applicability in the treatment of malignancies such as cancer has greatly improved the survival of patients and has been revolutionizing the field of cancer treatment [ 14 ].…”

“…Later on, the outcome of patients improved with the emergence of mAbs targeting the axis of PD-1/PD-L1. Currently, there are seven different IC inhibitors that have been approved for the treatment of patients as first- and second-line therapies [ 13 , 14 , 37 ]; however, there is a subset of individuals that still do not respond to this therapy by presenting de novo and/or adaptive responses [ 14 , 15 , 16 , 17 , 18 , 38 ]. For instance, treatment targeting anti-PD-1/PD-L1 therapy in certain types of cancers with microsatellite stability shows poor efficiency [ 39 ].…”

“…The recent introduction of monoclonal antibodies (mAbs) targeting immune checkpoints (ICs) as a treatment for cancer patients represents a possible therapy for EBV-associated diseases. However, this mAb therapy still needs improvement, since a group of patients showed serious adverse effects and/or did not respond to the actual mAb therapy [ 13 , 14 , 15 , 16 , 17 , 18 ]. Therefore, our review aims to summarize the progress made regarding the contribution of EBV infection to the expression of the IC indoleamine 2,3-dioxygenase (IDO) so far.…”

IDO1 Inhibition Reduces Immune Cell Exclusion Through Inducing Cell Migration While PD-1 Blockage Increases IL-6 and -8 Secretion From T Cells in Head and Neck Cancer

“…Thus, other immunotherapies that can modify the immune landscape of the tumor to enhance the effect of existing ICIs should be identified (11)(12)(13). A promising target molecule may be indoleamine 2,3-dioxygenase 1 (IDO1), a cytosolic heme-containing enzyme that catalyzes the initial step of tryptophan catabolism kynurenine and its other immunosuppressive catabolites (14). At present, the two most advanced and investigated drugs for IDO1 inhibition are indoximod and epacadostat (13).…”