Immunologic effects of locoregional therapies for unresectable hepatocellular carcinoma

Background and Aims The combination of locoregional therapies (LRT) with immune checkpoint inhibitors (ICI) in unresectable hepatocellular carcinoma (HCC) is expected to enhance immune-mediated anti-tumor effects. While clinical trials are underway, an unmet need exists to understand the immunological effects of LRT and how they evolve over time. This study aimed to longitudinally assess immune cell subpopulations and checkpoint expression post-LRT. Methods This prospective, single-center study (DRKS00026994) enrolled 128 consecutive patients with unresectable HCC, who underwent conventional transarterial chemoembolization (cTACE), interstitial high-dose-rate brachytherapy (iBT), or a combination of cTACE/iBT (07/2020-09/2021). Peripheral blood samples were collected at baseline, one day, and two months post-LRT. Immune cells were quantified using spectral flow cytometry. Immune cell subpopulations and checkpoint molecule expression were compared longitudinally and among treatment groups. Cluster analyses were employed to explore immune profiles and their relationship with treatment response. Results Changes in absolute immune cell counts were detected one day post-LRT, which largely diminished by two months. Myeloid populations increased significantly, while most lymphoid cells decreased post-LRT. However, relative proportions of anti-tumoral CD56 diminished NK cells (Cohen's D 0.40, 95%-CI [0.19-0.61], p<0.01), CD8 + T cells (Cohen's D 0.15 [-0.06-0.35], p=0.01), and CTLA-4 expression on T cells (CD4 + : Cohen's D 0.54 [0.33-0.75], p<0.01; CD8 + : Cohen's D 0.15 [0.36-0.78], p<0.01) were upregulated at one day, particularly after cTACE. Cluster analysis distinguished responders from non-responders based on distinct immune profiles. Conclusions LRT induce an early pro-inflammatory immune response with increased myeloid, CTLA-4+ T cells, and cytotoxic lymphocytes, particularly after cTACE These findings support the potential of immune profiling to guide personalized combination strategies with LRT and systemic immunotherapies. Impact and implications Combining locoregional therapies (LRT) with immune checkpoint inhibitors (ICI) in unresectable hepatocellular carcinoma (HCC) compromises to enhance immune-mediated anti-tumor effects, however, potential immunological targets yet remain unknown. Immune profiling could be facilitated as a tool to predict tumor response to LRT and may inform personalized treatment planning selecting patients who may benefit from an additional ICI therapy. The study's design may guide future investigations to identify the temporal dynamics of immune cell alterations following LRT to identify the appropriate time point to co-administer ICI application. Clinical trial number DRKS00026994 (https://drks.de/search/de/trial/DRKS00026994)