High serum IL-6 correlates with reduced clinical benefit of atezolizumab and bevacizumab in unresectable hepatocellular carcinoma.

Background & Aims: We elucidated the clinical and immunologic implications of serum IL-6 levels in patients with unresectable hepatocellular carcinoma (HCC) treated with atezolizumab and bevacizumab (Ate/Bev).
Methods: We prospectively enrolled 165 patients with unresectable HCC (discovery cohort: 84 patients from three centres; validation cohort: 81 patients from one centre). Baseline blood samples were analysed using a flow cytometric bead array. The tumour immune microenvironment was analysed using RNA sequencing.
Results: In the discovery cohort, clinical benefit 6 months (CB _6m ) was defined as complete or partial response, or stable disease for ≥6 months. Among various blood-based biomarkers, serum IL-6 levels were significantly higher in participants without CB _6m than in those with CB _6m (mean 11.56 vs . 5.05 pg/ml, p  = 0.02). Using maximally selected rank statistics, the optimal cut-off value for high IL-6 was determined as 18.49 pg/ml, and 15.2% of participants were found to have high IL-6 levels at baseline. In both the discovery and validation cohorts, participants with high baseline IL-6 levels had a reduced response rate and worse progression-free and overall survival after Ate/Bev treatment compared with those with low baseline IL-6 levels. In multivariable Cox regression analysis, the clinical implications of high IL-6 levels persisted, even after adjusting for various confounding factors. Participants with high IL-6 levels showed reduced interferon-γ and tumour necrosis factor-α secretion from CD8 ⁺ T cells. Moreover, excess IL-6 suppressed cytokine production and proliferation of CD8 ⁺ T cells. Finally, participants with high IL-6 levels exhibited a non-T-cell-inflamed immunosuppressive tumour microenvironment.
Conclusions: High baseline IL-6 levels can be associated with poor clinical outcomes and impaired T-cell function in patients with unresectable HCC after Ate/Bev treatment.
Impact and Implications: Although patients with hepatocellular carcinoma who respond to treatment with atezolizumab and bevacizumab exhibit favourable clinical outcomes, a fraction of these still experience primary resistance. We found that high baseline serum levels of IL-6 correlate with poor clinical outcomes and impaired T-cell response in patients with hepatocellular carcinoma treated with atezolizumab and bevacizumab.
Competing Interests: HJC has a consulting or advisory role at Eisai, Roche, Bayer, ONO, MSD, BMS, Celgene, Sanofi, Servier, AstraZeneca, Sillajen, Menarini, and GreenCross Cell, and has received research grants from Roche, Dong-A ST, and Boryung Pharmaceuticals. CK has a consulting or advisory role at Roche, ONO, MSD, BMS, Oncocross, Virocure, Sillajen, and Panolos Biosciences, and has received research grants from Boryung Pharmaceuticals, Oncocross, Sillajen, and Virocure. JC has a consulting or advisory role at Roche, MSD China, Eisai, and Servier, and has received research grants from Bayer. VEG is an employee of F. Hoffmann-La Roche Ltd. and has stock options from F. Hoffmann-La Roche Ltd. The other authors have no potential conflicts of interest to disclose. Please refer to the accompanying ICMJE disclosure forms for further details.
(© 2023 The Author(s).)