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

Hannah Yang; Beodeul Kang; Yeonjung Ha; Sung Hwan Lee; Ilhwan Kim; Hyeyeong Kim; Won Suk Lee; Gwangil Kim; Sanghoon Jung; Sun Young Rha; Vincent E Gaillard; Jaekyung Cheon; Chan Kim; Hong Jae Chon

doi:10.1016/j.jhepr.2023.100672

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

JHEP Rep. 2023 Jan 16;5(4):100672. doi: 10.1016/j.jhepr.2023.100672. eCollection 2023 Apr.

Authors

Hannah Yang¹, Beodeul Kang^{1

2}, Yeonjung Ha³, Sung Hwan Lee⁴, Ilhwan Kim⁵, Hyeyeong Kim⁶, Won Suk Lee¹, Gwangil Kim⁷, Sanghoon Jung⁸, Sun Young Rha^{2

9}, Vincent E Gaillard¹⁰, Jaekyung Cheon¹, Chan Kim¹, Hong Jae Chon¹

Affiliations

¹ Medical Oncology, Department of Internal Medicine, CHA Bundang Medical Center, CHA University, Seongnam, Republic of Korea.
² Yonsei Graduate School, Yonsei University College of Medicine, Seoul, Republic of Korea.
³ Department of Gastroenterology, CHA Bundang Medical Center, Seongnam, Republic of Korea.
⁴ Department of Surgery, CHA Bundang Medical Center, Seongnam, Republic of Korea.
⁵ Division of Oncology, Department of Internal Medicine, Inje University College of Medicine, Haeundae Paik Hospital, Busan, Republic of Korea.
⁶ Department of Internal Medicine, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan, Republic of Korea.
⁷ Department of Pathology, CHA Bundang Medical Center, Seongnam, Republic of Korea.
⁸ Department of Radiology, CHA Bundang Medical Center, Seongnam, Republic of Korea.
⁹ Division of Medical Oncology, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Republic of Korea.
¹⁰ F. Hoffmann-La Roche Ltd., Basel, Switzerland.

Abstract

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.

Keywords: AFP, alpha-foetoprotein; Ate/Bev, atezolizumab and bevacizumab; Atezolizumab; BCLC, Barcelona Clinic Liver Cancer; Bevacizumab; CB6m, clinical benefit 6 months; CONSORT, Consolidated Standards of Reporting Trials; CR, complete response; CRAFITY, C-reactive protein and AFP in immunotherapy; CTLA-4, cytotoxic T-lymphocyte-associated protein 4; DC, dendritic cell; ECOG, Eastern Cooperative Oncology Group; FFPE, formalin-fixed paraffin-embedded; HCC, hepatocellular carcinoma; HR, hazard ratio; Hepatocellular carcinoma; IFN-γ, interferon-γ; IL-6; Immunotherapy; MDSC, myeloid-derived suppressor cell; MSI, microsatellite instability; MVI, macrovascular invasion; ORR, objective response rate; OS, overall survival; PBMC, peripheral blood mononuclear cell; PD, progressive disease; PD-1, programmed-death-1; PD-L1, programmed-death ligand-1; PFS, progression-free survival; PR, partial response; RECIST, Response Evaluation Criteria in Solid Tumours; SD, stable disease; TME, tumour microenvironment; TNF-α, tumour necrosis factor-α; VEGF, vascular endothelial growth factor.