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Abstract LB-184: The immunotherapeutic role of indoleamine 2,3-dioxygenase (IDO) in head and neck squamous cell carcinoma: a systematic review

Background: Novel cancer immunotherapy includes application of immune checkpoint inhibitors to the treatment of solid tumors. The body’s own immune system is thereby harnessed to tip the balance in favor of antitumor activity. The intracellular enzyme indoleamine 2,3-dioxygenase (IDO) is a critical regulator of the tumor microenvironment (TME) via tryptophan metabolism. Programmed death protein 1 (PD-1) and programmed death-ligand 1 (PD-L1) are immune checkpoints involved in T-cell inhibition and immunosuppression. Another immune checkpoint, IDO1, breaks down tryptophan into its metabolites which results in immunosuppression in the TME. Aim: To assess the evidence on IDO in head and neck squamous cell carcinoma (HNSCC). Methods: Medline, EMBASE using Ovid, Scopus, Web of Science, Cochrane Library databases, and ClinicalTrials.gov were searched from inception until present day. Results: We included 32 studies. Of those, 5 involved cell lines, 7 assessed tumor immunohistochemistry, 6 measured IDO gene transcription, and 14 reported on clinical trials. The human cell lines studied commonly were SCC4, SCC15, and SCC25 in which IDO expression and activation by the Stimulator of Interferon Genes (STING) pathway played a central role. Retrospective immunohistochemistry studies of lower lip, oral cavity, tongue, tonsil, and larynx found that relatively high IDO expression correlated with worse survival. Gene transcription studies showed increased IDO in tumors that expressed PD-L1 and harbored human papillomavirus (HPV). Phase I/II clinical trials showed 1) objective responses (34%) and disease control rates (62%) for IDO1 inhibitor in combination with a PD-1 inhibitor, 2) consistent safety profile in combination versus monotherapy, and 3) IDO gene expression as a predictive biomarker for response to PD-L1 therapy. Conclusions: IDO is integral to TME immunity in HNSCC particularly in HPV positive tumors, modulating existing therapies and application in combinatorial immunotherapy. Retrospective studies have shown the presence of IDO in the TME and suggest a link to prognosis and prediction of HNSCC treatment outcome. However, the exact mechanism of IDO-driven immune modulation in the HNSCC TME remains unclear. We now require prospective longitudinal studies to track IDO activity and expression throughout HNSCC treatment, thence optimise IDO-based immunotherapy. Citation Format: Daniel J. Lin, James C. Ng, Lei Huang, Max Robinson, James O9Hara, Janet A. Wilson, Andrew L. Mellor. The immunotherapeutic role of indoleamine 2,3-dioxygenase (IDO) in head and neck squamous cell carcinoma: a systematic review [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-184.