Characterisation of PD-L1-positive subsets of microsatellite-unstable colorectal cancers

Background: The aim of this study was to reveal the clinicopathological and molecular characteristics of microsatellite instability-high (MSI-H) colorectal cancers (CRCs) showing programmed death ligand-1 (PD-L1) positivity, which are good candidates for anti-PD-1/PD-L1 immunotherapy. Methods: The PD-L1 expression status of 208 MSI-H CRCs was retrospectively analysed using immunohistochemistry. PD-L1 positivity in tumour cells (PD-L1+(T)) and PD-L1 positivity in immune cells (PD-L1+(I)) were separately evaluated. Results: Programmed death ligand-1 positivity in tumour cells and PD-L1+(I) were observed in 26 (12.5%) and 62 (29.8%) MSI-H CRCs, respectively, and occasionally overlapped ( n =12; 5.8%). Programmed death ligand-1 positivity tumours in MSI-H CRCs were significantly associated with older age, female sex, non-mucinous-type poor differentiation, infiltrating growth, tumour budding, advanced stage, CpG island methylator phenotype-high, MLH1 promoter methylation, and BRAF V600E mutations. However, PD-L1+(I) MSI-H CRCs were characterised by high-density tumour-infiltrating immune cells, including T cells and macrophages, and intense peritumoural lymphoid reactions. In patients with stage IV MSI-H CRCs who had undergone metastatectomy ( n =4), the PD-L1 status of primary tumours was maintained in corresponding distant metastatic lesions. Conclusions: In MSI-H CRCs, PD-L1+(T) and PD-L1+(I) are linked to a sporadic hypermethylated subtype and an immune cell-rich subtype, respectively. Potential differential therapeutic implications of PD-L1+(T) and PD-L1+(I) in CRCs should be further investigated.