Multimodal sequencing of neoadjuvant nivolumab treatment in hepatocellular carcinoma reveals cellular and molecular immune landscape for drug response
Abstract A striking characteristic of liver cancer is its extensive heterogeneity, particularly with regard to its varied response to immunotherapy. In this study, we employed multimodal sequencing approaches to explore the various aspects of neoadjuvant nivolumab treatment in liver cancer patients....
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BMC
2025-04-01
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| Series: | Molecular Cancer |
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| Online Access: | https://doi.org/10.1186/s12943-025-02314-w |
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| author | Fanhong Zeng Qingyang Zhang Yu-Man Tsui Huanhuan Ma Lu Tian Abdullah Husain Jingyi Lu Joyce Man-Fong Lee Vanilla Xin Zhang Po-Man Li Gary Cheuk-Hang Cheung Tan-To Cheung Daniel Wai-Hung Ho Irene Oi-Lin Ng |
| author_facet | Fanhong Zeng Qingyang Zhang Yu-Man Tsui Huanhuan Ma Lu Tian Abdullah Husain Jingyi Lu Joyce Man-Fong Lee Vanilla Xin Zhang Po-Man Li Gary Cheuk-Hang Cheung Tan-To Cheung Daniel Wai-Hung Ho Irene Oi-Lin Ng |
| author_sort | Fanhong Zeng |
| collection | DOAJ |
| description | Abstract A striking characteristic of liver cancer is its extensive heterogeneity, particularly with regard to its varied response to immunotherapy. In this study, we employed multimodal sequencing approaches to explore the various aspects of neoadjuvant nivolumab treatment in liver cancer patients. We used spatially-resolved transcriptomics, single- and bulk-cell transcriptomics, and TCR clonotype analyses to examine the spatiotemporal dynamics of the effects of nivolumab. We observed a significantly higher clonal expansion of T cells in the tumors of patients who responded to the treatment, while lipid accumulation was detected in those of non-responders, likely due to inherent differences in lipid metabolic processes. Furthermore, we found a preferential enrichment of T cells, which was associated with a better drug response. Our results also indicate a functional antagonism between tumor-associated macrophages (TAMs) and CD8 cells and their spatial separation. Notably, we identified a UBASH3B/NR1I2/CEACAM1/HAVCR2 signaling axis, highlighting the intense communication among TAMs, tumor cells, and T-cells that leads to pro-tumorigenic outcomes resulting in poorer nivolumab response. In summary, using integrative multimodal sequencing investigations, combined with the multi-faceted exploration of pre- and post-treatment samples of neoadjuvant nivolumab-treated HCC patients, we identified useful mechanistic determinants of therapeutic response. We also reconstructed the spatiotemporal model that recapitulates the physiological restoration of T cell cytotoxicity by anti-PD1 blockade. Our findings could provide important biomarkers and explain the mechanistic basis differentiating the responders and non-responders. |
| format | Article |
| id | doaj-art-4e3611dba85d4818894d547f7c9603c9 |
| institution | OA Journals |
| issn | 1476-4598 |
| language | English |
| publishDate | 2025-04-01 |
| publisher | BMC |
| record_format | Article |
| series | Molecular Cancer |
| spelling | doaj-art-4e3611dba85d4818894d547f7c9603c92025-08-20T02:28:02ZengBMCMolecular Cancer1476-45982025-04-0124112410.1186/s12943-025-02314-wMultimodal sequencing of neoadjuvant nivolumab treatment in hepatocellular carcinoma reveals cellular and molecular immune landscape for drug responseFanhong Zeng0Qingyang Zhang1Yu-Man Tsui2Huanhuan Ma3Lu Tian4Abdullah Husain5Jingyi Lu6Joyce Man-Fong Lee7Vanilla Xin Zhang8Po-Man Li9Gary Cheuk-Hang Cheung10Tan-To Cheung11Daniel Wai-Hung Ho12Irene Oi-Lin Ng13Department of Pathology, The University of Hong KongDepartment of Pathology, The University of Hong KongDepartment of Pathology, The University of Hong KongDepartment of Pathology, The University of Hong KongDepartment of Pathology, The University of Hong KongDepartment of Pathology, The University of Hong KongDepartment of Pathology, The University of Hong KongDepartment of Pathology, The University of Hong KongDepartment of Pathology, The University of Hong KongDepartment of Pathology, The University of Hong KongDepartment of Pathology, The University of Hong KongState Key Laboratory of Liver Research, The University of Hong KongDepartment of Pathology, The University of Hong KongDepartment of Pathology, The University of Hong KongAbstract A striking characteristic of liver cancer is its extensive heterogeneity, particularly with regard to its varied response to immunotherapy. In this study, we employed multimodal sequencing approaches to explore the various aspects of neoadjuvant nivolumab treatment in liver cancer patients. We used spatially-resolved transcriptomics, single- and bulk-cell transcriptomics, and TCR clonotype analyses to examine the spatiotemporal dynamics of the effects of nivolumab. We observed a significantly higher clonal expansion of T cells in the tumors of patients who responded to the treatment, while lipid accumulation was detected in those of non-responders, likely due to inherent differences in lipid metabolic processes. Furthermore, we found a preferential enrichment of T cells, which was associated with a better drug response. Our results also indicate a functional antagonism between tumor-associated macrophages (TAMs) and CD8 cells and their spatial separation. Notably, we identified a UBASH3B/NR1I2/CEACAM1/HAVCR2 signaling axis, highlighting the intense communication among TAMs, tumor cells, and T-cells that leads to pro-tumorigenic outcomes resulting in poorer nivolumab response. In summary, using integrative multimodal sequencing investigations, combined with the multi-faceted exploration of pre- and post-treatment samples of neoadjuvant nivolumab-treated HCC patients, we identified useful mechanistic determinants of therapeutic response. We also reconstructed the spatiotemporal model that recapitulates the physiological restoration of T cell cytotoxicity by anti-PD1 blockade. Our findings could provide important biomarkers and explain the mechanistic basis differentiating the responders and non-responders.https://doi.org/10.1186/s12943-025-02314-wImmunotherapySpatial transcriptomicsLiver cancer |
| spellingShingle | Fanhong Zeng Qingyang Zhang Yu-Man Tsui Huanhuan Ma Lu Tian Abdullah Husain Jingyi Lu Joyce Man-Fong Lee Vanilla Xin Zhang Po-Man Li Gary Cheuk-Hang Cheung Tan-To Cheung Daniel Wai-Hung Ho Irene Oi-Lin Ng Multimodal sequencing of neoadjuvant nivolumab treatment in hepatocellular carcinoma reveals cellular and molecular immune landscape for drug response Molecular Cancer Immunotherapy Spatial transcriptomics Liver cancer |
| title | Multimodal sequencing of neoadjuvant nivolumab treatment in hepatocellular carcinoma reveals cellular and molecular immune landscape for drug response |
| title_full | Multimodal sequencing of neoadjuvant nivolumab treatment in hepatocellular carcinoma reveals cellular and molecular immune landscape for drug response |
| title_fullStr | Multimodal sequencing of neoadjuvant nivolumab treatment in hepatocellular carcinoma reveals cellular and molecular immune landscape for drug response |
| title_full_unstemmed | Multimodal sequencing of neoadjuvant nivolumab treatment in hepatocellular carcinoma reveals cellular and molecular immune landscape for drug response |
| title_short | Multimodal sequencing of neoadjuvant nivolumab treatment in hepatocellular carcinoma reveals cellular and molecular immune landscape for drug response |
| title_sort | multimodal sequencing of neoadjuvant nivolumab treatment in hepatocellular carcinoma reveals cellular and molecular immune landscape for drug response |
| topic | Immunotherapy Spatial transcriptomics Liver cancer |
| url | https://doi.org/10.1186/s12943-025-02314-w |
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