Reponse to neo-adjuvant chemotherapy in oesophageal adenocarcinoma is predicted by PD-L1 expression

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Introduction

Mounting evidence supports the role of the immune response in improving response to chemotherapy. Immune checkpoints programmed-death 1 (PD-1) and its ligand PD-L1 downregulate T cell activation characterised by an “exhausted” ineffective tumour immune infiltrate.

Aims

We investigated the role of PD-L1 gene and protein expression, and tumour-infiltrating lymphocytes, in response to neoadjuvant chemotherapy (NAC) in oesophageal adenocarcinoma (OAC).

Methods

Formaline fixed paraffin embedded pre-treatment endoscopic OAC biopsies were obtained for 273 patients, treated with cisplatin-based neoadjuvant chemotherapy followed by surgical resection at 4 UK centres between 2003 and 2014. Transciptional profiling was performed using the Almac Diagnostics Xcel array, and PD-L1 expression levels determined. Response was assessed by tumour regression grade (TRG). Immunohistochemistry for PD-L1 and CD8 was performed in matched post-chemotherapy resection specimens in 135 patients.

Results

High PD-L1 expression in the pre-chemotherapy biopsies was associated with with response to NAC (TRG ≤2; p = 0.023). Stromal and tumoural PD-L1 and CD8 expression were significantly associated (p < 0.001). Positive stromal CD8 expression significantly correlated with pathological response (p = 0.0081). Patients with PD-L1 IHC positivity in tumor cells demonstrated improved relapse-free survival (Hazard Ratio 0.314; 95% CI 0.099-0.997; p=0.049). The combination of PD-L1 and CD8 positivity did not have a stronger effect than PD-L1 expression alone (p = 0.106).

Conclusion

High PD-L1 expression may aid selection of conventional anti-cancer treatment in oesophageal adenocarcinoma. Anti-PD-1 targeted therapy should be considered in esophageal adenocarcinoma and further exploration of potential predictive biomarkers is required.