Expression of PD-L1 and PD-1 in Chemoradiotherapy-Naïve Esophageal and Gastric Adenocarcinoma: Relationship With Mismatch Repair Status and Survival

Abstract

Background: The outlook for patients with esophageal and gastric (EG) cancer remains poor. Hence, there is a compelling need to identify novel treatment strategies and complementary biomarkers. Programmed death ligand 1 (PD-L1) and mismatch repair deficiency (dMMR) are putative biomarkers of response to immune-checkpoint blockade, but their prognostic value and interrelationship in EG cancer have been sparsely investigated. Methods: Immunohistochemical expression of PD-L1 on tumour cells (TC) and tumour-infiltrating immune cells (TIC), and of PD-1 (programmed death receptor 1) on TIC was assessed using tissue microarrays with primary tumours and a subset of paired lymph node metastases from a consecutive, retrospective cohort of 174 patients with chemoradiotherapy-naïve EG adenocarcinoma. MMR proteins MLH1, PMS2, MSH2, and MSH6 were assessed by immunohistochemistry. The total number (intratumoural, tumour-adjacent, and stromal) of CD8+ T cells in each core was calculated by automated analysis. Results: High PD-L1 expression on both TC and TIC, but not PD-1 expression, was significantly associated with dMMR. PD-L1 expression on TIC was significantly higher in lymph node metastases than in primary tumours. High expression of PD-L1 or PD-1 on TIC was significantly associated with a prolonged survival, the former independently of established prognostic factors. A significant stepwise positive association was found between CD8+ T cells and categories of PD-L1 expression on TIC. Conclusion: PD-L1 expression on TIC is higher in lymph node metastases compared to primary tumours, correlates with dMMR, and is an independent factor of prolonged survival in patients with chemoradiotherapy-naïve EG adenocarcinoma. These findings suggest that PD-L1 expression on TIC may be a useful biomarker for identifying patients who may not need additional chemo- or chemoradiotherapy, and who may benefit from PD-1/PD-L1 immune-checkpoint blockade.

Keywords: MMR status; MSI status; PD-1; PD-L1; esophageal cancer; gastric cancer; the cancer genome atlas.

Figures

Figure 1

Immunohistochemical expression of PD-1 and PD-L1 in the primary tumour (left) and a paired lymph node metastasis (right) from an esophageal (cardia Siewert 1) pT3N3M0 tumour. PD-1 and PD-L1 positivity was denoted in >50% of the immune cells, and PD-L1 positivity was denoted in >50% of the tumour cells. Arrowheads with solid lines denote PD-L1 positive tumour cells and arrowheads with dashed lines denote PD-L1 positive immune cells. In general, PD-L1 positive immune cells in the lymph nodes were located in the vincinity of the metastatic deposits.

Figure 2

Bar charts visualising the distribution of PD-L1 expression on (A) tumour cells and (B) tumour-infiltrating immune cells and (C) the distribution of PD-1 expression on tumour-infiltrating immune cells, in primary tumours and paired lymph node metastases, in the entire cohort; (A)p = 1.000, (B)p = 0.009, (C)p = 0.180.

Figure 3

Kaplan-Meier analysis of OS in strata according to immunohistochemical staining categories of (A) PD-L1 expression on, (B) PD-L1 expression on, and (C) PD-1 expression on in the entire cohort. (A)<1% = ref, 1–4% p = 0.285, 5–9% p = 0.815, 10–49% p = 0.721, 50–100% p = 0.763, (B)<10% = ref, 10–49% p = 0.512, 50–100% p = 0.014, (C)<10% = ref, 10–49% p = 0.003, 50–100% p = 0.842.

Figure 4

Kaplan-Meier estimates of TTR in strata according to immunohistochemical staining categories of (A) PD-L1 expression on, (B) PD-L1 expression on and (C) PD-1 expression on in the entire cohort. (A) <1% = ref, 1–4% p = 0.803, 5–9% p = 0.244, 10–49% p = 0.815, 50–100% p = 0.603, (B) <10% = ref, 10–49% p = 0.484, 50–100% p = 0.010, (C) <10% = ref, 10–49% p = 0.000, 50–100% p = 0.824.

Figure 5

Kaplan-Meier estimates of OS in strata according to high and low (A) PD-L1 and (B) PD-1 mRNA expression in gastric cancer and high and low (C) PD-L1 and (D) PD-1 mRNA expression, in esophageal cancer, in TCGA. (A)p = 0.116, (B)p = 0.041, (C)p = 0.168, (D)p = 0.053.

Figure 6

Kaplan-Meier estimates of OS in strata according to MMR status in (A) the entire cohort, p = 0.626, (B) esophageal tumours, p = 0.824, and (C) gastric tumours, p = 0.740.

Figure 7

Box plots visualising the associations of CD8+ T cells with (A) PD-L1 expression on tumour cells and (B) PD-L1 expression on tumour-infiltrating immune cells and (C) PD-1 expression on tumour-infiltrating immune cells, in primary tumours in the entire cohort.