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.

Keywords: cholangiocarcinoma; immune checkpoint inhibitor; tissue-resident memory T cells; tumour-infiltrating lymphocytes.