Implication of CD69(+)CD103(+) tissue-resident-like CD8(+) T cells as a potential immunotherapeutic target for cholangiocarcinoma

Abstract

Background The heterogeneous immune landscapes of intrahepatic cholangiocarcinoma (ICC) remain largely unknown. Here we aimed to investigate the implications of tissue-resident memory (TRM)-related features of tumour-infiltrating CD8(+) T cells (CD8(+) TILs) from ICC patients. Methods From ICC patients, we obtained blood samples and ICC surgical specimens (n = 33). We performed multicolour flow cytometry, multiplexed immunohistochemistry and RNA sequencing. Results When compared to peripheral CD8(+) T cells, the CD8(+) TILs included significantly higher proportions of the CD69(+)CD103(-) and CD69(+)CD103(+) TRM-like subsets (P < .001 for both). Relative to CD69(-) and CD69(+)CD103(-) cells, the CD69(+)CD103(+) CD8(+) TILs harboured higher levels of T-cell markers representing tumour specificity (ie CD39), proliferation (ie Ki-67) and T-cell activation (ie HLA-DR and CD38) (all P < .001). Moreover, compared to the stroma, the tumour margin and core density each had a significantly higher density of CD103(+) CD8(+) TILs (P < .001 for both). ICCs with high proportions of CD69(+)CD103(+) cells displayed higher levels of parameters associated with response to immune checkpoint inhibitors (ICIs)-including number of CD8(+) TIL infiltrates (P = .019), PD-L1 expression in the tumour (P = .046) and expression of the T cell-inflamed gene signature (P < .001). ICCs with lower proportions of CD69(+)CD103(+) CD8(+) TILs exhibited significant enrichment of genes related to the Wnt/beta-catenin (P < .001) and TGF-beta pathways (P = .002). Conclusion CD69(+)CD103(+) TRM-like CD8(+) TILs represent prominent tumour-specific immune responses and hold promise as a potential therapeutic target in ICC patients. Differential TRM-related features of ICCs may help develop future immunotherapeutic strategies such as maximizing TRM responses or inhibiting pathways contributing to immune evasion.