Immunosuppression

Blockade

Amino acid

Biology

Immune checkpoint

Kynurenine

Receptor

Cancer research

Biochemistry

Indoleamine 2,3-dioxygenase

Immunology

Ipilimumab

Immune system

Pembrolizumab

Tumor microenvironment

Tryptophan

Internal medicine

Pharmacology

PD-L1

Medicine

Immunotherapy

Cancer

Cancer Treatment Reviews

Strategies for unlocking immunosuppression in the tumor microenvironment have been investigated to overcome resistance to first-generation immune checkpoint blockade with anti- programmed cell death protein 1 (PD-1)/ programmed death-ligand 1 (PD-L1) and anti-cytotoxic T-lymphocyte associated protein 4 (CTLA-4) agents. Indoleamine 2,3-dioxygenase (IDO) 1, an enzyme catabolizing tryptophan to kynurenine, creates an immunosuppressive environment in preclinical studies. Early phase clinical trials investigating inhibition of IDO1, especially together with checkpoint blockade, provided promising results. Unfortunately, the phase 3 trial of the IDO1 inhibitor epacadostat combined with the PD-1 inhibitor pembrolizumab did not show clinical benefit when compared with pembrolizumab monotherapy in patients with advanced malignant melanoma, which dampened enthusiasm for IDO inhibitors. Even so, several molecules, such as the aryl hydrocarbon receptor and tryptophan 2,3-dioxygenase, were reported as additional potential targets for the modulation of the tryptophan pathway, which might enhance clinical effectiveness. Furthermore, the combination of IDO pathway blockade with agents inhibiting other signals, such as those generated by PIK3CA mutations that may accompany IDO1 upregulation, may be a novel way to enhance activity. Importantly, IDO1 expression level varies by tumor type and among patients with the same tumor type, suggesting that patient selection based on expression levels of IDO1 may be warranted in clinical trials.

Indoleamine 2,3-dioxygenase (IDO) inhibitors and cancer immunotherapy