EBV+ and MSI Gastric Cancers Harbor High PD-L1/PD-1 Expression and High CD8+ Intratumoral Lymphocytes

Abstract

Both EBV+ and MSI gastric cancers (GCs) have high lymphoid infiltration which is rare in MSS/EBV− cancers. PD-L1/PD-1 interaction leads to a down-regulated immune response and it is one of the most promising targets for gastric cancer immunotherapy. PD-L1/PD-1 and CD8 expression were immunohistochemically investigated in a series of 169 FFPE GCs, including 33 EBV+, 59 MSI and 77 MSS/EBV− cases. PD-L1 membrane immunoreactivity in more than 5% of tumor cells was present in 31/169 GCs and was associated with high levels of CD8 intraepithelial lymphocytes (TILs; p < 0.001). PD-L1+ cases were mainly poorly differentiated (71%), intestinal type (85%) and high lymphoid response (HLR; 90%) tumors. PD-L1 expression was only present in EBV⁺ (46%), MSI (24%) and rare MSS/EBV− (3%) GCs with high CD8+ TILs (p < 0.001). Despite being associated with a better prognosis both in the whole series (p < 0.05) and in the MSI subset, PD-L1 is not an independent prognostic factor. PD-L1 gene amplification was detected in 3/17 cases, including 2/7 EBV+ and 1/8 MSI GC. PD-1⁺ TILs were significantly higher in EBV⁺ than MSI and MSS/EBV− cases. PD-L1/PD-1 pathway is selectively activated in HLR GCs and could be considered an emerging therapeutic target, particularly for EBV and MSI GCs.

Prognostic Biomarkers in Early-stage Gastric Adenocarcinoma Treated With Adjuvant Chemoradiotherapy

“…Our findings are in line with the frequency of EBV-positivity and microsatellite instability (MSI) in The Cancer Genome Atlas (TCGA) cohort (24). EBV-positive and dMMR or MSI-high gastric cancer has been associated with high intratumoral CD8 TIL density (26)(27)(28). In our study, we indeed found a significant correlation between EBV-positivity and intratumoral CD8 TILs.…”

MMR Deficiency is Homogeneous in Pancreatic Carcinoma and Associated with High Density of Cd8-Positive Lymphocytes

“…The significant association between MMR deficiency and high number of intratumoral CD8-positive lymphocytes found for pancreatic cancer in this study is consistent with earlier data from colorectal, endometrial and stomach cancer. [19][20][21]61 Elevated lymphocyte counts may represent evidence for immunogenic events having occurred in a cancer, a feature that is believed to be essential for successful therapy with immune checkpoint inhibitors. The significantly higher CD8 density in MMR deficient compared with MMR intact pancreatic cancers may thus provide an additional hint towards a potential utility of immune checkpoint inhibitors in pancreatic cancers as suggested by the successful treatment of several cancers in a site-agnostic clinical trial.…”

EBV-associated gastric cancer evades T-cell immunity by PD-1/PD-L1 interactions

“…There are several reports that PD-L1 was overexpressed in GC with EBV or MSIhigh [8-12, 33, 34]. Both EBVaGC and MSI-high GC are accompanied by abundant lymphocyte infiltration which can produce IFN-γ [28,29,[34][35][36][37]. Though it might be possible that MSI-high GC uses the same mechanism as EBVaGC, further studies are needed to clarify the role of PD-1/PD-L1 interaction in MSI-high GC.…”