Indoleamine 2,3-dioxygenase 1 and Programmed Cell Death-ligand 1 Co-expression Predicts Poor Pathologic Response and Recurrence in Esophageal Squamous Cell Carcinoma after Neoadjuvant Chemoradiotherapy

Sha Zhou, Lei Zhao, Zhaohui Liang, Songran Liu, Yong Li, Shiliang Liu, Hong Yang, Mengzhong Liu, Mian Xi, Sha Zhou, Lei Zhao, Zhaohui Liang, Songran Liu, Yong Li, Shiliang Liu, Hong Yang, Mengzhong Liu, Mian Xi

Abstract

This study aimed to investigate the impact of indoleamine 2,3-dioxygenase 1 (IDO1) expression, programmed cell death-ligand 1 (PD-L1) expression, CD8+ tumor-infiltrating lymphocyte (TIL) status, and their combination on pathologic complete response (pCR) and recurrence in esophageal squamous cell carcinoma (ESCC) treated with neoadjuvant chemoradiotherapy (CRT). Indoleamine 2,3-dioxygenase 1, PD-L1, and CD8+ TIL statuses were evaluated by immunohistochemical analysis on pre-CRT biopsies of 158 patients. Sixty-eight patients (43.0%) achieved pCR after neoadjuvant CRT and 48 patients (30.4%) developed recurrences after surgery. IDO1 and PD-L1 proteins were co-expressed in 28 patients (17.7%). Indoleamine 2,3-dioxygenase 1 positive patients showed a significantly lower pCR rate than IDO1 negative patients (28.6% vs. 51.0%, P = 0.007). Similarly, PD-L1 high expression was significantly negatively correlated with pCR rate (27.3% vs. 51.5%, P = 0.004). On multivariate analysis, IDO1 expression was an independent prognostic factor for developing recurrences. Stratification analysis revealed that patients with co-expression of IDO1 and PD-L1 were significantly associated with a lower pCR rate and worse recurrence-free survival than those with one or none positive protein. In conclusion, IDO1 and PD-L1 co-expression could predict poor pathologic response and high risk of recurrence in ESCC after neoadjuvant CRT, indicating a subset of patients who may benefit from CRT combined with immunotherapy.

Keywords: IDO1; PD-L1; esophageal squamous cell carcinoma; neoadjuvant chemoradiotherapy; pathologic response.

Conflict of interest statement

All authors have no conflicts of interest to declare.

Figures

Figure 1
Figure 1
Comparison of indoleamine 2,3-dioxygenase 1 (IDO1) (A) and programmed cell death-ligand 1 (PD-L1) (B) mRNA expression levels in esophageal squamous cell carcinoma tissues and matched normal esophageal mucosa by qRT-PCR.
Figure 2
Figure 2
IDO1 and PD-L1 expression and CD8+ tumor-infiltrating lymphocyte (TIL) status in esophageal squamous cell carcinoma. (A) Positive immunohistochemical staining pattern for IDO1; (B) Negative immunohistochemical staining pattern for IDO1; (C) Positive immunohistochemical staining pattern for PD-L1; (D) Negative immunohistochemical staining pattern for PD-L1; (E) Pattern for high CD8+ TIL density; (F) Pattern for low CD8+ TIL density.
Figure 3
Figure 3
Comparison of pathologic complete response rates by IDO1 expression status (A), PD-L1 expression status (B), and CD8 density (C).
Figure 4
Figure 4
Comparison of overall survival (A) and recurrence-free survival (B) between patients with positive or negative IDO1 expression. Comparison of overall survival (C) and recurrence-free survival (D) between patients with positive or negative PD-L1 expression. Comparison of overall survival (E) and recurrence-free survival (F) between patients with high or low CD8 density.
Figure 5
Figure 5
Comparison of pathologic complete response rates according to the co-expression status of IDO1 and PD-L1 (A). Kaplan-Meier curves for overall survival (B) and recurrence-free survival (C) in patients with esophageal squamous cell carcinoma according to the co-expression status of IDO1 and PD-L1. Type I: IDO1 (+)/PD-L1 (+); Type II: IDO1 (−)/PD-L1 (+) or IDO1 (+)/PD-L1 (−); Type III: IDO1 (−)/PD-L1 (−).

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