Japan Digestive Disease Week 2025
International Session (Symposium)1 (JSH, JSGE)
October 30, 9:30–12:00, Room 11 (Portopia Hotel South Wing Topaz)
IS-S1-6_H
Spatial CD8+ T Cell Distribution as a Predictive Biomarker for Atezolizumab Plus Bevacizumab Efficacy in Advanced Hepatocellular Carcinoma
- 1
- Department of Gastroenterology, Graduate School of Medicine, Chiba University
- 2
- Division of Digestive and Liver Diseases, Department of Internal Medicine, The University of Texas Southwestern Medical Center
- 3
- Department of Pathology, International University of Health and Welfare, School of Medicine, Narita Hospital
Background and Aims: Atezolizumab plus bevacizumab (Atez/Bev) improves prognosis in advanced hepatocellular carcinoma (HCC), but its therapeutic mechanisms remain unclear. This study aims to elucidate the molecular basis of treatment efficacy and identify predictive biomarkers through a comprehensive tumor microenvironment (TME) analysis.
Methods: We analyzed biopsy samples from 94 advanced HCC patients before Atez/Bev using immunohistochemistry, RNA sequencing, flow cytometry, and multiplexed imaging. Spatial analysis focused on CD8+ T cells and effector regulatory T (eTreg) cells, with longitudinal assessment at baseline, during treatment, and upon disease progression.
Results: Higher PD-1 positivity in CD8+ T cells correlated with prolonged progression-free survival, while CD8+ T cell density alone was not predictive. Furthermore, diffuse infiltration of CD8+ T cells within the tumor parenchyma, rather than confinement to fibrous stroma, was associated with improved treatment response. PD-1 positivity in eTreg cells was not prognostic. Notably, bevacizumab suppressed eTreg activation induced by PD-L1 blockade, mitigating potential immunosuppressive effects.
Conclusions: Spatial analysis of CD8+ T cell localization and distribution within the tumor parenchyma is a practical predictor of Atez/Bev efficacy and can be implemented in routine histopathology. Additionally, the suppression of eTreg activation by bevacizumab highlights a synergistic mechanism underlying Atez/Bev therapy, providing insights for future combination immunotherapies in advanced HCC.
Methods: We analyzed biopsy samples from 94 advanced HCC patients before Atez/Bev using immunohistochemistry, RNA sequencing, flow cytometry, and multiplexed imaging. Spatial analysis focused on CD8+ T cells and effector regulatory T (eTreg) cells, with longitudinal assessment at baseline, during treatment, and upon disease progression.
Results: Higher PD-1 positivity in CD8+ T cells correlated with prolonged progression-free survival, while CD8+ T cell density alone was not predictive. Furthermore, diffuse infiltration of CD8+ T cells within the tumor parenchyma, rather than confinement to fibrous stroma, was associated with improved treatment response. PD-1 positivity in eTreg cells was not prognostic. Notably, bevacizumab suppressed eTreg activation induced by PD-L1 blockade, mitigating potential immunosuppressive effects.
Conclusions: Spatial analysis of CD8+ T cell localization and distribution within the tumor parenchyma is a practical predictor of Atez/Bev efficacy and can be implemented in routine histopathology. Additionally, the suppression of eTreg activation by bevacizumab highlights a synergistic mechanism underlying Atez/Bev therapy, providing insights for future combination immunotherapies in advanced HCC.
- Index Term 1: Advanced hepatocellular carcinoma
- Index Term 2: Tumor microenvironment