Peripheral T lymphocyte immune characteristics dictate response to transarterial chemoembolization in unresectable hepatocellular carcinoma.

Abstract

Background: Although transcatheter arterial chemoembolization (TACE) is one of the first-line treatments for unresectable HCC (uHCC) patients, its overall efficacy varies significantly. Therefore, the identification of reliable biomarkers capable of effectively distinguishing TACE-responsive populations is clinically critical.

Objectives: Our research aims to investigate T-lymphocyte subpopulations and associated pathways in peripheral blood that contribute to TACE refractoriness, as well as to develop effective methods for predicting TACE efficacy.

Design: This is an observational study.

Methods: A total of 50 patients who underwent standard TACE-based therapy between January 2020 and December 2022 were included in this study. TACE response was evaluated within 1-3 months following two consecutive TACE sessions. Patients with TACE failure were assigned to the Non-Response group, whereas the remaining were categorized into the Response group. Blood samples were collected prior to treatment and subsequently analyzed using flow cytometry and RNA sequencing. Predictors were analyzed using univariate and multivariate analyses within the bivariate logistic regression models. Pathway enrichment analysis was performed using gene set enrichment analysis (GSEA).

Results: A total of 24 of 50 (48%) exhibited TACE failure (Non-Response). Baseline peripheral T-lymphocyte analysis revealed that the Non-Response group had a higher abundance of senescent phenotype (T_Senescence, CD27^-CD28^-) in both CD4/CD8⁺ T cells (p < 0.0001), but a lower proportion of memory stem cell (T_SCM) subpopulation (CD4⁺ T_SCM: p = 0.0411; CD8⁺ T_SCM: p < 0.0001). Furthermore, in CD8⁺ T cells, they exhibited higher expression of exhaustion marks (PD-1: p = 0.0005; LAG-3: p = 0.0026; TIGIT: p = 0.0014) and significantly lower production of effector molecules (TNF-α: p < 0.0001; IFN-γ: p = 0.0018; GZMB: p < 0.0001). Transcriptomics revealed that the Response group was enriched in pathways associated with energy and drug metabolism. Univariate and multivariate analyses demonstrated that the baseline CD8⁺ T_SCM and CD8⁺ T_Senescence subpopulations were significant predictive factors for TACE efficacy.

Conclusion: Our study demonstrated significant differences in the immune characteristics of peripheral T lymphocytes between the Non-Response and Response groups. The CD8⁺ T_SCM and CD8⁺ T_Senescence subsets are potential predictors of TACE efficacy and long-term survival. These insights into peripheral blood T lymphocytes offer valuable evidence to help clinicians more effectively identify potential TACE-responsive populations, predict survival, and develop personalized treatment regimens for patients with uHCC.