Four distinct immune microenvironment subtypes in gastric adenocarcinoma with special reference to microsatellite instability

INTRODUCTION: Programmed death-ligand 1 (PD-L1) can be overexpressed in tumours other than Epstein-Barr virus (EBV)-positive (EBV(+)) or microsatellite instability-high (MSI-H) gastric cancer (GC) subtypes. We aimed to determine the tumour immune microenvironment (TME) classification of GC to better understand tumour–immune interactions and help patient selection for future immunotherapy with special reference to MSI-H. METHODS: Immunohistochemistry (IHC) for PD-L1 and CD8(+) T cells in three distinct subtypes of GC (43 EBV(+), 79 MSI-H and 125 EBV(−)/MSS) were performed and analysed. In 66 MSI-H GC, mutation counts were compared with PD-L1 expression and survival of the patients. RESULTS: GC TME divided by PD-L1 IHC and tumour-infiltrating lymphocytes (TIL) measured by intratumoural CD8 density showed: (1) about 40% of GC are type I (PD-L1(+)/TIL(+)) consisting ~70% of MSI-H or EBV(+) GC, and ~15% of EBV(−)/microsatellite stable (MSS) GC patients show the best survival in both disease-free (HR 2.044) and overall survival (HR 1.993); this type would respond to a checkpoint blockade therapy; (2) almost 30% of GC are type II (PD-L1(−)/TIL(−)) with the worst survival; (3) approximately 10% of GC are type III (PD-L1(+)/TIL(−)); and (4) up to 20% are type IV (PD-L1(−)/TIL(+)) and, unexpectedly, ~25% of EBV(+) or MSI-H GC are within this subtype. In MSI-H GC, frequent frameshift mutations were observed in ARID1A, RNF43, NF1, MSH6, BRD3, NCOA3, BCORL1, TNKS2 and NPM1 and the numbers of frameshift mutation correlated significantly with PD-L1 expression (P<0.05). DISCUSSION: GC can be classified into four TME types based on PD-L1 and TIL, and numbers of frameshift mutation correlate well with PD-L1 expression in MSI-H GC.