Prognostic implications of immune classification using IDO1 expression in extrahepatic bile duct carcinoma

Abstract

Indoleamine 2, 3-dioxygenase 1 (IDO1) is an immunomodulatory enzyme that catalyzes the degradation of tryptophan to kynurenine and induces immune tolerance in tumor cells. The effects of IDO1 on extrahepatic bile duct carcinoma (EHBDC) are poorly understood. Therefore, the present study aimed to investigate the expression and prognostic significance of IDO1 in EHBDC. An immunohistochemical microarray analysis of IDO1 expression was performed for 76 surgically resected cases of EHBDC. CD8⁺ tumor infiltrating lymphocytes (TILs) were also investigated through a combination analysis with IDO1 expression. IDO1 was highly expressed in 25 of 76 (32.9%) cases. High expression of IDO1 was associated with decreased numbers of CD8⁺ TILs (P=0.008), a higher pN category (P=0.007), an advanced overall stage (P=0.001) and frequent recurrence (P=0.018). When IDO1 expression was further stratified with CD8⁺ TIL state, the IDO1^high/CD8^low subgroup was decreased in terms of overall survival (P=0.025) and disease-free survival (P=0.015) compared with IDO1^high/CD8^high, IDO1^low/CD8^high and IDO1^low/CD8^low subgroups. High IDO1 expression was associated with a decreased number of CD8⁺ TILs and associated with a poor prognosis. As IDO1 may be a new target of immunotherapy applications, IDO1/CD8⁺ TIL subgrouping can be a useful prognostic and predictive tool in patients with EHBDC.

Keywords: 3-dioxygenase 1; bile duct cancer; indoleamine 2; tumor infiltrating lymphocytes.

Figure 1.

Immunohistochemical stains for IDO1 and CD8 expression. (A) A case with high IDO1 expression in the cytoplasm of tumor epithelial cells (indicated by arrowhead) with (B) rare CD8-positive TILs (indicated by dotted circle). (C) Another case with low IDO1 expression (indicated by arrowhead) with (D) frequent CD8-positive TILs (indicated by dotted circle). Scale bar, 200 µm; original magnification, ×200). IDO1, indoleamine 2, 3-dioxygenase 1; TILs, tumor infiltrating lymphocytes.

Figure 2.

Kaplan-Meier curves according to IDO1 and CD8⁺ TILs expression. Patients with high IDO1 expression show poor clinical outcomes for (A) disease-free survival and (B) overall survival compared with low IDO1 expression. Patients with high CD8⁺ TIL expression tend to have a more favorable (C) disease-free survival and (D) overall survival compared with those with low CD8⁺ TIL expression. IDO1, indoleamine 2, 3-dioxygenase 1; TILs, tumor infiltrating lymphocytes.

Figure 3.

Kaplan-Meier curves according to immune subgroups using combined IDO1 and CD8⁺ TILs expression. The IDO1^high/CD8^low subgroup demonstrated the worst prognosis, while the IDO1^low/CD8^high subgroup demonstrates the best clinical outcome for (A) disease-free survival and (B) overall survival compared with IDO1^low/CD8^low and IDO1^high/CD8^high subgroups. Patients with IDO1^high/CD8^low expression demonstrated a statistically favorable survival outcome for (C) disease-free survival and (D) overall survival compared with those in the other three groups. IDO1, indoleamine 2, 3-dioxygenase 1; TILs, tumor infiltrating lymphocytes.