The efficacy of atezolizumab plus bevacizumab for advanced hepatocellular carcinoma in relation to tumor-infiltrating lymphocytes.

[BACKGROUND & AIMS] Atezolizumab plus bevacizumab (Atez/Bev) improves prognosis in advanced hepatocellular carcinoma, but its mechanisms remain unclear. This study aims to identify predictive biomarkers through a comprehensive analysis of the tumor microenvironment.

[METHODS] Biopsy samples from 94 patients with advanced hepatocellular carcinoma before Atez/Bev were analyzed using immunohistochemistry, bulk RNA-sequencing, flow cytometry, and multiplexed imaging. The tumor microenvironment assessment included profiling of CD8 T cells and effector regulatory T (eTreg) cells. Immune dynamics were examined across baseline, in-treatment, and progression samples from each patient.

[RESULTS] We found favorable progression-free survival to be associated with a high percentage of programmed death-1 (PD-1) positivity in CD8 T cells but not with CD8 T-cell density. PD-1 positivity in CD8 T cells was dichotomized at the median (58%). Building upon PD-1 positivity in CD8 T cells, predominant and diffuse infiltration of CD8 T cells within the tumor parenchyma was shown to be associated with improved treatment response. PD-1 positivity in eTreg cells was not associated with prognosis. Finally, we found that Bev, an antivascular endothelial growth factor antibody, suppresses the eTreg-cell activation induced by programmed death-ligand 1 (PD-L1) blockade.

[CONCLUSIONS] We demonstrate that immunohistochemistry analysis to determine the localization and distribution of CD8 T cells within the tumor is a viable means of predicting treatment efficacy for Atez/Bev and provides a valuable framework for future trial design. This is an exploratory analysis with no current consequences in clinical practice. Future studies should confirm the results in an external cohort.

[IMPACT AND IMPLICATIONS] This study demonstrates that the localization and distribution pattern of CD8 T cells within the tumor parenchyma are predictors of atezolizumab plus bevacizumab treatment outcomes in advanced hepatocellular carcinoma. The study further reveals that bevacizumab counteracts the potentially unfavorable influence of programmed death-ligand 1 blockade by suppressing effector regulatory T-cell activation. These findings provide both a valuable guide for determining treatment strategies in routine clinical practice and a foundation for future immunotherapy development for the treatment of advanced hepatocellular carcinoma.

[CLINICAL TRIALS REGISTRATION] The study protocol was registered on the University Hospital Medical Information Network Clinical Trials Registry (UMIN-CTR) (UMIN000047701).