Multimodal molecular landscape of response to Y90-resin microsphere radioembolization followed by nivolumab for advanced hepatocellular carcinoma
Background Combination therapy with radioembolization (yttrium-90)-resin microspheres) followed by nivolumab has shown a promising response rate of 30.6% in a Phase II trial (CA209-678) for advanced hepatocellular carcinoma (HCC); however, the response mechanisms and relevant biomarkers remain unkno...
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| Format: | Article |
| Language: | English |
| Published: |
BMJ Publishing Group
2023-08-01
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| Series: | Journal for ImmunoTherapy of Cancer |
| Online Access: | https://jitc.bmj.com/content/11/8/e007106.full |
| _version_ | 1797729145968394240 |
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| author | David Tai Fei Yao Joycelyn Lee Su Pin Choo Joe Yeong Jeffrey Chun Tatt Lim Han Chong Toh Xinru Lim Jiangfeng Ye Denise Goh Tony Kiat-Hon Lim Mai Chan Lau Timothy Wai Ho Shuen Weiwei Zhai Jia Qi Lim Lawrence Cheung Neslihan Arife Kaya Cheryl Zi Jin Phua Felicia Yu Ting Wee Craig Ryan Joseph Zhen Wei Neo Kelvin S H Loke Apoorva Gogna May Yin Lee Axel Hilmer Yun Shen Chan Wai Leong Tam |
| author_facet | David Tai Fei Yao Joycelyn Lee Su Pin Choo Joe Yeong Jeffrey Chun Tatt Lim Han Chong Toh Xinru Lim Jiangfeng Ye Denise Goh Tony Kiat-Hon Lim Mai Chan Lau Timothy Wai Ho Shuen Weiwei Zhai Jia Qi Lim Lawrence Cheung Neslihan Arife Kaya Cheryl Zi Jin Phua Felicia Yu Ting Wee Craig Ryan Joseph Zhen Wei Neo Kelvin S H Loke Apoorva Gogna May Yin Lee Axel Hilmer Yun Shen Chan Wai Leong Tam |
| author_sort | David Tai |
| collection | DOAJ |
| description | Background Combination therapy with radioembolization (yttrium-90)-resin microspheres) followed by nivolumab has shown a promising response rate of 30.6% in a Phase II trial (CA209-678) for advanced hepatocellular carcinoma (HCC); however, the response mechanisms and relevant biomarkers remain unknown.Methods By collecting both pretreatment and on-treatment samples, we performed multimodal profiling of tissue and blood samples and investigated molecular changes associated with favorable responses in 33 patients from the trial.Results We found that higher tumor mutation burden, NCOR1 mutations and higher expression of interferon gamma pathways occurred more frequently in responders. Meanwhile, non-responders tended to be enriched for a novel Asian-specific transcriptomic subtype (Kaya_P2) with a high frequency of chromosome 16 deletions and upregulated cell cycle pathways. Strikingly, unlike other cancer types, we did not observe any association between T-cell populations and treatment response, but tumors from responders had a higher proportion of CXCL9+/CXCR3+ macrophages. Moreover, biomarkers discovered in previous immunotherapy trials were not predictive in the current cohort, suggesting a distinctive molecular landscape associated with differential responses to the combination therapy.Conclusions This study unraveled extensive molecular changes underlying distinctive responses to the novel treatment and pinpointed new directions for harnessing combination therapy in patients with advanced HCC. |
| first_indexed | 2024-03-12T11:25:49Z |
| format | Article |
| id | doaj.art-14c8d7451ab74713956c9bc91a18b071 |
| institution | Directory Open Access Journal |
| issn | 2051-1426 |
| language | English |
| last_indexed | 2024-03-12T11:25:49Z |
| publishDate | 2023-08-01 |
| publisher | BMJ Publishing Group |
| record_format | Article |
| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj.art-14c8d7451ab74713956c9bc91a18b0712023-09-01T08:55:07ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262023-08-0111810.1136/jitc-2023-007106Multimodal molecular landscape of response to Y90-resin microsphere radioembolization followed by nivolumab for advanced hepatocellular carcinomaDavid Tai0Fei Yao1Joycelyn Lee2Su Pin Choo3Joe Yeong4Jeffrey Chun Tatt Lim5Han Chong Toh6Xinru Lim7Jiangfeng Ye8Denise Goh9Tony Kiat-Hon Lim10Mai Chan Lau11Timothy Wai Ho Shuen12Weiwei Zhai13Jia Qi Lim14Lawrence Cheung15Neslihan Arife Kaya16Cheryl Zi Jin Phua17Felicia Yu Ting Wee18Craig Ryan Joseph19Zhen Wei Neo20Kelvin S H Loke21Apoorva Gogna22May Yin Lee23Axel Hilmer24Yun Shen Chan25Wai Leong Tam26Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), SingaporeGenome Institute of Singapore (GIS), Agency for Science(A*STAR), Technology and Research, SingaporeDivision of Medical Oncology, National Cancer Centre Singapore, SingaporeDivision of Medical Oncology, National Cancer Centre Singapore, SingaporeDepartment of Anatomical Pathology, Singapore General Hospital, SingaporeInstitute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), SingaporeDivision of Medical Oncology, National Cancer Centre Singapore, SingaporeInstitute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), SingaporeInstitute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), SingaporeInstitute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), SingaporeDepartment of Anatomical Pathology, Singapore General Hospital, SingaporeSingapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR), SingaporeDivision of Medical Oncology, National Cancer Centre Singapore, SingaporeKey Laboratory of Zoological Systematics and Evolution, Institute of Zoology, Chinese Academy of Sciences, Beijing, ChinaGenome Institute of Singapore (GIS), Agency for Science(A*STAR), Technology and Research, SingaporeInstitute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), SingaporeGenome Institute of Singapore (GIS), Agency for Science(A*STAR), Technology and Research, SingaporeGenome Institute of Singapore (GIS), Agency for Science(A*STAR), Technology and Research, SingaporeInstitute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), SingaporeInstitute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), SingaporeInstitute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), SingaporeDuke NUS Medical School, SingaporeDepartment of Vascular and Interventional Radiology, Singapore General Hospital, SingaporeGenome Institute of Singapore (GIS), Agency for Science(A*STAR), Technology and Research, SingaporeInstitute of Pathology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Koln, Cologne, GermanyGuangzhou Laboratory, Guangzhou International Bio Island, Guangzhou, Guangdong Province, ChinaGenome Institute of Singapore (GIS), Agency for Science(A*STAR), Technology and Research, SingaporeBackground Combination therapy with radioembolization (yttrium-90)-resin microspheres) followed by nivolumab has shown a promising response rate of 30.6% in a Phase II trial (CA209-678) for advanced hepatocellular carcinoma (HCC); however, the response mechanisms and relevant biomarkers remain unknown.Methods By collecting both pretreatment and on-treatment samples, we performed multimodal profiling of tissue and blood samples and investigated molecular changes associated with favorable responses in 33 patients from the trial.Results We found that higher tumor mutation burden, NCOR1 mutations and higher expression of interferon gamma pathways occurred more frequently in responders. Meanwhile, non-responders tended to be enriched for a novel Asian-specific transcriptomic subtype (Kaya_P2) with a high frequency of chromosome 16 deletions and upregulated cell cycle pathways. Strikingly, unlike other cancer types, we did not observe any association between T-cell populations and treatment response, but tumors from responders had a higher proportion of CXCL9+/CXCR3+ macrophages. Moreover, biomarkers discovered in previous immunotherapy trials were not predictive in the current cohort, suggesting a distinctive molecular landscape associated with differential responses to the combination therapy.Conclusions This study unraveled extensive molecular changes underlying distinctive responses to the novel treatment and pinpointed new directions for harnessing combination therapy in patients with advanced HCC.https://jitc.bmj.com/content/11/8/e007106.full |
| spellingShingle | David Tai Fei Yao Joycelyn Lee Su Pin Choo Joe Yeong Jeffrey Chun Tatt Lim Han Chong Toh Xinru Lim Jiangfeng Ye Denise Goh Tony Kiat-Hon Lim Mai Chan Lau Timothy Wai Ho Shuen Weiwei Zhai Jia Qi Lim Lawrence Cheung Neslihan Arife Kaya Cheryl Zi Jin Phua Felicia Yu Ting Wee Craig Ryan Joseph Zhen Wei Neo Kelvin S H Loke Apoorva Gogna May Yin Lee Axel Hilmer Yun Shen Chan Wai Leong Tam Multimodal molecular landscape of response to Y90-resin microsphere radioembolization followed by nivolumab for advanced hepatocellular carcinoma Journal for ImmunoTherapy of Cancer |
| title | Multimodal molecular landscape of response to Y90-resin microsphere radioembolization followed by nivolumab for advanced hepatocellular carcinoma |
| title_full | Multimodal molecular landscape of response to Y90-resin microsphere radioembolization followed by nivolumab for advanced hepatocellular carcinoma |
| title_fullStr | Multimodal molecular landscape of response to Y90-resin microsphere radioembolization followed by nivolumab for advanced hepatocellular carcinoma |
| title_full_unstemmed | Multimodal molecular landscape of response to Y90-resin microsphere radioembolization followed by nivolumab for advanced hepatocellular carcinoma |
| title_short | Multimodal molecular landscape of response to Y90-resin microsphere radioembolization followed by nivolumab for advanced hepatocellular carcinoma |
| title_sort | multimodal molecular landscape of response to y90 resin microsphere radioembolization followed by nivolumab for advanced hepatocellular carcinoma |
| url | https://jitc.bmj.com/content/11/8/e007106.full |
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