Strong Correlation of Indoleamine 2,3-Dioxygenase 1 Expression with Basal-Like Phenotype and Increased Lymphocytic Infiltration in Triple-Negative Breast Cancer

Abstract

Indoleamine 2,3-dioxygenase 1 (IDO1) is an immunosuppressive enzyme involved in tumor immune escape. Blockade of the IDO1 pathway is an emerging modality of cancer immunotherapy. Triple-negative breast cancer (TNBC) lacks established therapeutic targets and may be a good candidate for this novel immunotherapeutic agent. The purpose of this study was to evaluate the clinicopathologic characteristics of the IDO1-expressing TNBC subset. A tissue microarray was constructed from 200 patients with TNBC. Immunohistochemistry (IHC) for IDO1 and TNBC molecular subtype-surrogate markers (AR, GCDFP-15, claudin-3, E-cadherin, CK5/6, and EGFR) was performed using this tissue microarray. Real-time polymerase chain reaction was performed to confirm the IDO1 mRNA expression level in 16 fresh-frozen TNBC samples. Two hundred TNBCs were classified into four subtypes based on surrogate IHC results: 22 luminal androgen receptor type (11.0%), 23 claudin-low type (11.4%), 103 basal-like type (51.5%), and 52 mixed type (26.0%). IDO1 positivity (defined as expression of >10% tumor cells) was observed in 37% of all TNBCs. IDO1 IHC expression was well correlated with mRNA expression. IDO1 positivity was significantly associated with smaller tumor size, dense stromal lymphocytic infiltration, and basal-like phenotype; however, it did not affect the patients' prognosis. IDO1 expression in basal-like TNBCs is considered an immune inhibitory signal that counterbalances active immunity and may reflect the high mutational load of these tumors. Our results suggest which patients with TNBC would be more efficaciously treated with IDO1 blockade.

The prognostic value of IDO expression in solid tumors: a systematic review and meta-analysis

“…Significantly reduced heterogeneity in the prospective studies suggested that the type and quality of included literature may have affected the level of heterogeneity on OS. Since there was no enough information, our meta-analysis excluded some studies, and most of these studies were consistent with our results [45][46][47]. Only one study showed that high IDO mRNA expression was associated with favorable prognostic value in basal-like breast carcinoma, but this study only provided metastasis-free survival data in basal-like breast carcinoma [48].…”

PD‐L1 and IDO expression in cervical and vulvar invasive and intraepithelial squamous neoplasias: implications for combination immunotherapy

“…Subsequent studies in murine models have revealed that IDO plays a key role in preventing a host of autoimmune conditions . Work in malignancy has revealed IDO expression in a variety of solid tumour types, including non‐small‐cell lung carcinoma, colorectal carcinoma, breast carcinoma and a variety of gynaecological malignancies . Furthermore, multiple studies have shown enhanced IDO expression at the tumour–stromal interface and in areas of lymphocytic infiltration, suggesting an adaptive mechanism of immune evasion similar to that described with PD‐L1 .…”

Immune Landscape of Breast Cancers

“…It is therefore not surprising that tumors with high TIL infiltrate will also have an increase in the expression of PD-L1 and IDO. A recent study by Kim et al, where IDO1 protein expression was studied in 200 TNBC patients, found that over 50% of basal-like TNBC expressed IDO1 [ 43 ]. Epacadostat is an IDO1 inhibitor which has been shown to increase and restore the proliferation of dendritic cells, NK and T cells, but reduce Tregs.…”