# Immunologic effects of locoregional therapies for unresectable hepatocellular carcinoma

## TL;DR

This study explores how locoregional therapies affect the immune system in patients with unresectable liver cancer, finding early immune changes that may help guide future treatment combinations.

## Contribution

The study provides new insights into the immune response dynamics following locoregional therapies, particularly highlighting differences between treatment types and their impact on immune cell profiles.

## Key findings

- Most immune cell changes peaked one day after therapy and returned to baseline by two months.
- cTACE induced a stronger inflammatory immune response compared to interstitial brachytherapy.
- CD8+ T cells and CTLA-4 expression were notably upregulated after therapy, and immune profiling could distinguish responders from non-responders.

## Abstract

The combination of locoregional therapies (LRT) with immune checkpoint inhibitors (ICIs) in unresectable hepatocellular carcinoma (HCC) is expected to enhance immune-mediated anti-tumor effects. Although clinical trials are underway, an unmet need exists to understand the immunological effects of LRT and how they evolve. This study aimed to longitudinally assess immune cell subpopulations and checkpoint expression after LRT.

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 and iBT (from July 2020 to September 2021). Peripheral blood samples were collected at baseline, 1 day after LRT, and 2 months after 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 used to explore immune profiles and their relationship with treatment response.

Changes in absolute immune cell counts were detected 1 day after LRT, which largely diminished by 2 months. Myeloid populations increased significantly, whereas most lymphoid cells decreased after LRT. However, relative proportions of anti-tumoral CD56diminished NK cells (Cohen’s D = 0.40, 95% CI 0.19–0.61, p <0.01), CD8+ T cells (Cohen’s D = 0.15, 95% CI -0.06 to 0.35, p = 0.01), and CTLA-4 expression on T cells (CD4+: Cohen’s D = 0.54, 95% CI 0.33–0.75, p <0.01; CD8+: Cohen’s D = 0.15, 95% CI 0.36–0.78, p <0.01) were upregulated at 1 day, particularly after cTACE. Cluster analysis distinguished responders from non-responders based on distinct immune profiles.

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.

Combining locoregional therapies (LRT) with immune checkpoint inhibitors (ICI) in unresectable hepatocellular carcinoma (HCC) aims to enhance immune-mediated anti-tumor effects. However, potential immunological targets 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 the ICI application.

DRKS00026994 (https://drks.de/search/de/trial/DRKS00026994).

Image 1

•ImmuMITT addresses the unmet need to study the immunologic effects of locoregional therapies.•Most immune cell changes peaked at 1 day after therapy and diminished by 2 months.•Compared with interstitial brachytherapy, cTACE led to a stronger inflammatory immune response.•CD8+ T cells and CTLA-4 expression were notably upregulated after therapy.•Profiling of immune cell dynamics differentiated responders from non-responders.

ImmuMITT addresses the unmet need to study the immunologic effects of locoregional therapies.

Most immune cell changes peaked at 1 day after therapy and diminished by 2 months.

Compared with interstitial brachytherapy, cTACE led to a stronger inflammatory immune response.

CD8+ T cells and CTLA-4 expression were notably upregulated after therapy.

Profiling of immune cell dynamics differentiated responders from non-responders.