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/β‐catenin ( P < .001) and TGF‐β 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.