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.

Molecular Classification of Gastric Cancer among Alaska Native People

“…In our study, PD-L1 expression in immune and tumor cells was observed in 17% of AN gastric cancer patients. A PD-L1 combined positive score greater than 1 was significantly correlated with MMR deficient patients, similar to previous studies in breast [65], colorectal [66], gastric [67], and esophageal cancers [68,69]. Moreover, in gastric cancer, it has been well-known that PD-L1+ tumors frequently have PIK3CA mutations, which are also strongly associated with MSI-high and EBV+ tumors [13,59,70,71], as we observed in our cohort.…”

Tumor-Associated CD68+, CD163+, and MARCO+ Macrophages as Prognostic Biomarkers in Patients With Treatment-Naïve Gastroesophageal Adenocarcinoma

“…In the present study, there were no significant associations between any of the investigated macrophage subsets and dMMR-status. However, expression of programmed death ligand-1 (PD-L1) on both tumor cells and immune cells has previously been shown to be strongly associated with dMMR-status in the present cohort (17), and in this study, significant associations were observed between CD163 + macrophage infiltration and PD-L1 expression on tumor cells, and between MARCO + macrophages and PD-L1 expression on both tumor cells and immune cells. Speculatively, these findings suggest that certain subsets of macrophages may be more relevant in the context of immunotherapy than for purposes of prognostication.…”

“…One patient received radiotherapy alone and another patient received chemotherapy alone. The cohort has been described in several previous studies (4,16,17). Clinical data regarding recurrence and vital status were obtained retrospectively from medical records, and the last update, with additional re-examination of some of the clinicopathological data, was performed in March 2016.…”

Preservation of Epstein–Barr virus status and mismatch repair protein status along the metastatic course of gastric cancer

“…Gastric cancer (GC) is currently the fifth most common cancer and the third most common cause of cancer‐related death worldwide 1,2 . Despite advances in therapy including neoadjuvant chemotherapy and human epidermal growth factor receptor 2 (HER2)‐targeted therapy, the overall 5‐year survival rate remains below 40% 3 . A high rate of resistance to conventional chemotherapy and the presence of locally advanced or metastatic disease at the time of initial diagnosis appear to be the major factors that contribute to the poor outcome 4 .…”