Patterns and prognostic values of programmed cell death-ligand 1 expression and CD8+ T-cell infiltration in small cell carcinoma of the esophagus: a retrospective analysis of 34 years of National Cancer Center data in China

Background: Small cell carcinoma of the esophagus (SCCE) is an extremely rare and highly aggressive neuroendocrine malignancy with a strikingly poor prognosis. Given the great clinical successes of checkpoint immunotherapies, we explored the expression profile and clinical significance of programmed cell death-ligand 1 (PD-L1) and CD8+ T cell in SCCE for the first time. Materials and methods: Tumor-infiltrating immune cells (TIICs) and tumor cells in postoperative, whole tumor sections from 147 SCCE patients were stained for PD-LI expression. We also evaluated each patient’s Combined Positive Score (CPS). Multiplex immunofluorescence staining (CD3, CD20, CD68, and PD-L1) was introduced to clarify the location of PD-L1. CD8 density was analyzed by digital imaging and analysis of entire slides. Clinical outcomes were tested for correlations with both PD-L1 expression and CD8 density. Results: No patients had PD-L1 expressed in their tumor cells. PD-L1+ expression in TIICs was detected in 65 patients (44.2%) and 42 (28.6%) exhibited CPS positivity. Multiplex immunofluorescence staining demonstrated that most of the PD-L1 was expressed on the CD68+ monocytes/macrophages. PD-L1 expression in the TIICs and CPS was found to be correlated with paraffin block age, tumor length, macroscopic type, T stage, and increased overall survival (OS). Expression of PD-L1 in TIICs showed significantly prolonged relapse-free survival (RFS). Increasing CD8 densities were associated with increased PD-L1 expression (Ptrend<0.0001). Multivariate regression confirmed that PD-L1 in TIICs and CD8 states were independent predictors of OS, and CD8 status were found to be independently predictive of RFS. A stratification based on PD-L1 and CD8 status was also significantly associated with both OS and RFS. Conclusion: Expression of PD-L1 was only detected in TIICs from approximately half of the patients with SCCEs. In SCCEs, PD-L1 and CD8 status are novel prognostic biomarkers and may inform the implementation of risk-related therapeutic strategies. SCCEs with higher CD8 infiltration also had higher expression of PD-L1, suggesting the development of resistance against adaptive immunity. These findings support the assertion that PD-L1/programmed cell death 1 inhibitors should be investigated in this rare malignancy.