Clinicopathologic implications of immune classification by PD-L1 expression and CD8-positive tumor-infiltrating lymphocytes in stage II and III gastric cancer patients

We co-assessed PD-L1 expression and CD8(+) tumor-infiltrating lymphocytes in gastric cancer (GC), and categorized into 4 microenvironment immune types. Immunohistochemistry (PD-L1, CD8, Foxp3, E-cadherin, and p53), PD-L1 mRNA in situ hybridization (ISH), microsatellite instability (MSI), and EBV ISH were performed in 392 stage II/III GCs treated with curative surgery and fluoropyrimidine-based adjuvant chemotherapy, and two public genome databases were analyzed for validation. PD-L1(+) was found in 98/392 GCs (25.0%). The proportions of immune types are as follows: PD-L1(+)/CD8(High,) 22.7%; PD-L1(−)/CD8(Low), 22.7%; PD-L1(+)/CD8(Low), 2.3%; PD-L1(−)/CD8(High), 52.3%. PD-L1(+)/CD8(High) type accounted for majority of EBV(+) and MSI-high (MSI-H) GCs (92.0% and 66.7%, respectively), and genome analysis from public datasets demonstrated similar pattern. PD-L1(−)/CD8(High) showed the best overall survival (OS) and PD-L1(−)/CD8(Low) the worst (P < 0.001). PD-L1 expression alone was not associated with OS, however, PD-L1(−)/CD8(High) type compared to PD-L1(+)/CD8(High) was independent favorable prognostic factor of OS by multivariate analysis (P = 0.042). Adaptation of recent molecular classification based on EBV, MSI, E-cadherin, and p53 showed no significant survival differences. These findings support the close relationship between PD-L1/CD8 status based immune types and EBV(+), MSI-H GCs, and their prognostic significance in stage II/III GCs.