Abstract
Expression of programmed cell death receptor ligand 1 (PD-L1) has been shown to be up-regulated in some gastric cancer patients and to correlate with the density of tumour infiltrating lymphocytes (TILs). However, conflicting results have been reported regarding TILs and the expression of PD-L1 as a prognostic marker for gastric cancer. We investigated the correlation of PD-L1 and TILs expression with clinicpathological characteristics in 105 well characterized gastric cancer patients. PD-L1 expression and CD3+ and CD8+ TILs were evaluated by fluorescent multiplex immunohistochemistry (mIHC) analysis. PD-L1 positive staining on tumour cells was observed in 35% cases and 48% cases showed PD-L1 expression on immune cells. Up-regulated PD-L1 expression on tumour cells and immune cells was associated with high density of pre-existing tumour infiltrating CD3+ and CD8+. In additional, more than 70% tumor infiltrating CD3+ cells were CD3+CD8+ cells. More than 60% PD-L1+ immune cells were PD-L1+CD3+CD8+ cells. PD-L1 expression in tumour cells was associated with poor prognosis and high density CD3+ and CD8+ TILs indicated improved overall survival in gastric cancer patients. Increased PD-L1 expression with low density CD3+ and CD8+ TILs had the shortest overall survival. In accordingly, PD-L1 absence with high density CD3+ and CD8+ TILs indicated the best prognosis. Combination of PD-L1 with pre-existing TILs may be more precise than PD-L1 alone for predicting survival in gastric cancer.
Highlights
Gastric cancer (GC) is the fourth most common cancer and second leading cause of cancer associated death for men and women worldwide [1, 2]
After examining all of the samples, we observed that of programmed cell death receptor ligand 1 (PD-L1) positive tumour cell samples, PD-L1 staining in 5% to 65% of tumor cells
Only 29% of the PD-L1 negative immune cell subset had a high density of CD3+ tumour infiltrating lymphocytes (TILs), 27% had a high density of CD8+ TILs. These results demonstrated that PD-L1 expression in tumor cells and immune cells was positively associated with the density of CD3+ and CD8+ TILs
Summary
Gastric cancer (GC) is the fourth most common cancer and second leading cause of cancer associated death for men and women worldwide [1, 2]. Blocking the programmed death 1 (PD-1) and it’s ligand 1 (PD-L1) immune checkpoint signalling to restore anti-tumour immunity has shown unprecedented rates of durable clinical responses in patients, notably in melanoma, renal, lung, prostate and bladder carcinomas [3,4,5,6]. Phase Ib studies of immunotherapy for advanced gastric cancer (KEYNOTE-012) are ongoing, with 22% of patients recorded having an overall response by blocking the PD-1/ PD-L1 immune checkpoint [7]. Several tumour types express PD-L1, including gastric cancer [8, 9]. Several studies have reported a correlation between PD-L1 expression and the prognosis of cancer patients, and that PD-L1 expression is a predictive biomarker for blocking PD-1/PD-L1 treatment response [13,14,15]. The clinical implications of the existence of PD-L1 in tumours and TILs in the tumour microenvironment are still controversial, and the prognostic potential of these factors is unclear
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