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
Affiliations
Hannah Yang
Medical Oncology, Department of Internal Medicine, CHA Bundang Medical Center, CHA University, Seongnam, Republic of Korea
Beodeul Kang
Medical Oncology, Department of Internal Medicine, CHA Bundang Medical Center, CHA University, Seongnam, Republic of Korea; Yonsei Graduate School, Yonsei University College of Medicine, Seoul, Republic of Korea
Yeonjung Ha
Department of Gastroenterology, CHA Bundang Medical Center, Seongnam, Republic of Korea
Sung Hwan Lee
Department of Surgery, CHA Bundang Medical Center, Seongnam, Republic of Korea
Ilhwan Kim
Division of Oncology, Department of Internal Medicine, Inje University College of Medicine, Haeundae Paik Hospital, Busan, Republic of Korea
Hyeyeong Kim
Department of Internal Medicine, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan, Republic of Korea
Won Suk Lee
Medical Oncology, Department of Internal Medicine, CHA Bundang Medical Center, CHA University, Seongnam, Republic of Korea
Gwangil Kim
Department of Pathology, CHA Bundang Medical Center, Seongnam, Republic of Korea
Sanghoon Jung
Department of Radiology, CHA Bundang Medical Center, Seongnam, Republic of Korea
Sun Young Rha
Yonsei Graduate School, Yonsei University College of Medicine, Seoul, Republic of Korea; Division of Medical Oncology, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Republic of Korea
Vincent E. Gaillard
F. Hoffmann-La Roche Ltd., Basel, Switzerland
Jaekyung Cheon
Medical Oncology, Department of Internal Medicine, CHA Bundang Medical Center, CHA University, Seongnam, Republic of Korea; Corresponding authors. Address: Medical Oncology, CHA Bundang Medical Center, 59 Yatap-ro, Bundang-gu, Seongnam 13496, Republic of Korea. Tel.: +82-31-780-7590; Fax: +82-31-780-3929.
Chan Kim
Medical Oncology, Department of Internal Medicine, CHA Bundang Medical Center, CHA University, Seongnam, Republic of Korea; Corresponding authors. Address: Medical Oncology, CHA Bundang Medical Center, 59 Yatap-ro, Bundang-gu, Seongnam 13496, Republic of Korea. Tel.: +82-31-780-7590; Fax: +82-31-780-3929.
Hong Jae Chon
Medical Oncology, Department of Internal Medicine, CHA Bundang Medical Center, CHA University, Seongnam, Republic of Korea; Corresponding authors. Address: Medical Oncology, CHA Bundang Medical Center, 59 Yatap-ro, Bundang-gu, Seongnam 13496, Republic of Korea. Tel.: +82-31-780-7590; Fax: +82-31-780-3929.
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 (CB6m) 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 CB6m than in those with CB6m (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.
