BTLA identifies dysfunctional PD-1-expressing CD4⁺ T cells in human hepatocellular carcinoma

Area of Science:

• Immunology
• Oncology
• T cell biology

Background:

• Immunotherapy targeting the PD-1/PD-L1 pathway shows variable responses in cancer patients.
• Distinct subsets of PD-1-expressing T cells may explain heterogeneous treatment outcomes.
• Markers to differentiate these T cell subsets in human cancers are currently unclear.

Purpose of the Study:

• To identify markers that demarcate distinct functional subsets within PD-1-expressing CD4+ T cells in hepatocellular carcinoma (HCC).
• To investigate the role of B and T lymphocyte attenuator (BTLA) in defining these subsets and their response to PD-1/PD-L1 blockade.

Main Methods:

• Flow cytometry analysis of PD-1 and BTLA expression on CD4+ T cells from HCC tumors and paired non-tumor liver tissue.
• Assessment of T cell function (IFNγ/TNF-α production, activation) in relation to BTLA and PD-1 expression.
• Evaluation of PD-L1 blockade effects on different T cell subsets.

Main Results:

• Both PD-1 and BTLA were upregulated on CD4+ T cells in HCC tumors compared to non-tumor liver.
• BTLA+PD-1+ CD4+ T cells were associated with advanced HCC stage.
• BTLA+PD-1+ cells represented a dysfunctional subset, while BTLA-PD-1+ cells were activated.
• PD-L1 blockade restored function in BTLA+PD-1+ cells but suppressed BTLA-PD-1+ cells.
• BTLA signaling was found to suppress CD4+ T cell function in HCC.

Conclusions:

• BTLA serves as a marker to distinguish functional subsets of PD-1-expressing CD4+ T cells in human cancer.
• Understanding these subsets can advance knowledge of inhibitory receptor blockade in immunotherapy.
• BTLA may represent a novel target for predicting response to PD-1/PD-L1-targeted immunotherapies.