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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 cohor...
Autores principales: | , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Elsevier
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9972403/ https://www.ncbi.nlm.nih.gov/pubmed/36866388 http://dx.doi.org/10.1016/j.jhepr.2023.100672 |
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author | Yang, Hannah Kang, Beodeul Ha, Yeonjung Lee, Sung Hwan Kim, Ilhwan Kim, Hyeyeong Lee, Won Suk Kim, Gwangil Jung, Sanghoon Rha, Sun Young Gaillard, Vincent E. Cheon, Jaekyung Kim, Chan Chon, Hong Jae |
author_facet | Yang, Hannah Kang, Beodeul Ha, Yeonjung Lee, Sung Hwan Kim, Ilhwan Kim, Hyeyeong Lee, Won Suk Kim, Gwangil Jung, Sanghoon Rha, Sun Young Gaillard, Vincent E. Cheon, Jaekyung Kim, Chan Chon, Hong Jae |
author_sort | Yang, Hannah |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-9972403 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Elsevier |
record_format | MEDLINE/PubMed |
spelling | pubmed-99724032023-03-01 High serum IL-6 correlates with reduced clinical benefit of atezolizumab and bevacizumab in unresectable hepatocellular carcinoma Yang, Hannah Kang, Beodeul Ha, Yeonjung Lee, Sung Hwan Kim, Ilhwan Kim, Hyeyeong Lee, Won Suk Kim, Gwangil Jung, Sanghoon Rha, Sun Young Gaillard, Vincent E. Cheon, Jaekyung Kim, Chan Chon, Hong Jae JHEP Rep Research Article 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. Elsevier 2023-01-16 /pmc/articles/PMC9972403/ /pubmed/36866388 http://dx.doi.org/10.1016/j.jhepr.2023.100672 Text en © 2023 The Author(s) https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). |
spellingShingle | Research Article Yang, Hannah Kang, Beodeul Ha, Yeonjung Lee, Sung Hwan Kim, Ilhwan Kim, Hyeyeong Lee, Won Suk Kim, Gwangil Jung, Sanghoon Rha, Sun Young Gaillard, Vincent E. Cheon, Jaekyung Kim, Chan Chon, Hong Jae High serum IL-6 correlates with reduced clinical benefit of atezolizumab and bevacizumab in unresectable hepatocellular carcinoma |
title | High serum IL-6 correlates with reduced clinical benefit of atezolizumab and bevacizumab in unresectable hepatocellular carcinoma |
title_full | High serum IL-6 correlates with reduced clinical benefit of atezolizumab and bevacizumab in unresectable hepatocellular carcinoma |
title_fullStr | High serum IL-6 correlates with reduced clinical benefit of atezolizumab and bevacizumab in unresectable hepatocellular carcinoma |
title_full_unstemmed | High serum IL-6 correlates with reduced clinical benefit of atezolizumab and bevacizumab in unresectable hepatocellular carcinoma |
title_short | High serum IL-6 correlates with reduced clinical benefit of atezolizumab and bevacizumab in unresectable hepatocellular carcinoma |
title_sort | high serum il-6 correlates with reduced clinical benefit of atezolizumab and bevacizumab in unresectable hepatocellular carcinoma |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9972403/ https://www.ncbi.nlm.nih.gov/pubmed/36866388 http://dx.doi.org/10.1016/j.jhepr.2023.100672 |
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