Associations of PD-1 and PD-L1 expression with mismatch repair status and prognosis in chemoradiotherapy-naïve esophageal and gastric adenocarcinoma.

Abstract

9 Background: Although neoadjuvant and/or adjuvant treatment enhances survival in patients with resectable esophageal and gastric (EG) cancer, the prognosis remains poor and there is a great need to identify novel treatment strategies and suitable biomarkers. Expression of programmed death ligand 1 (PD-L1) is, together with mismatch repair (MMR) status, a putative biomarker of response to immune-modulating therapies, but their prognostic value in EG cancer remains unclear. Therefore, the aim of this study was to examine the expression of PD-L1 in tumour cells (TC) and tumour-infiltrating immune cells (TIC), and the receptor PD-1 in TIC, in EG adenocarcinoma. Particular attention was given to their relationship with MMR status, and prognosis. Methods: PD-L1 and PD-1 expression in TC and/or TIC was assessed by immunohistochemistry (IHC) on tissue microarrays with primary tumours from a retrospective consecutive cohort of 174 patients with chemoradiotherapy-naïve resected EG adenocarcinoma. MMR status was determined by IHC. The prognostic value of PD-L1 and PD-1 was also examined at the mRNA level in 354 cases of gastric adenocarcinoma in The Cancer Genome Atlas. Results: PD-1 expression was not associated with MMR status, but PD-L1 expression in TC and TIC was significantly associated with MMR deficiency (p < 0.001 for both). Neither TC PD-L1 nor MMR status was prognostic. However, high PD-1 (10%) and PD-L1 ( > 50%) expression in TIC was significantly associated with a prolonged OS, the latter independently of other prognostic factors and MMR status (hazard ratio = 0.39, 95% confidence interval 0.15-0.99). Moreover, the prognostic value was only evident in MMR proficient tumours, and similar in esophageal and gastric tumours. At the transcript level, PD-L1 expression was not prognostic, but high PD-1 expression was significantly associated with a prolonged OS in gastric adenocarcinoma (p = 0.012). Conclusions: High expression of PD-L1 but not PD-1 is significantly associated with MMR deficiency in EG cancer. High PD-L1 expression in TIC but not in TC, or high PD-1 expression in TIC, signifies a prolonged survival, in particular in MMR proficient tumours.