Alteration in TET1 as potential biomarker for immune checkpoint blockade in multiple cancers
Abstract Background Immune checkpoint inhibitors (ICIs) have achieved impressive success in different cancer types, yet responses vary and predictive biomarkers are urgently needed. Growing evidence points to a link between DNA methylation and anti-tumor immunity, while clinical data on the associat...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMJ Publishing Group
2019-10-01
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| Series: | Journal for ImmunoTherapy of Cancer |
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| Online Access: | http://link.springer.com/article/10.1186/s40425-019-0737-3 |
| _version_ | 1818334746277576704 |
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| author | Hao-Xiang Wu Yan-Xing Chen Zi-Xian Wang Qi Zhao Ming-Ming He Ying-Nan Wang Feng Wang Rui-Hua Xu |
| author_facet | Hao-Xiang Wu Yan-Xing Chen Zi-Xian Wang Qi Zhao Ming-Ming He Ying-Nan Wang Feng Wang Rui-Hua Xu |
| author_sort | Hao-Xiang Wu |
| collection | DOAJ |
| description | Abstract Background Immune checkpoint inhibitors (ICIs) have achieved impressive success in different cancer types, yet responses vary and predictive biomarkers are urgently needed. Growing evidence points to a link between DNA methylation and anti-tumor immunity, while clinical data on the association of genomic alterations in DNA methylation-related genes and ICI response are lacking. Methods Clinical cohorts with annotated response and survival data and matched mutational data from published studies were collected and consolidated. The predictive function of specific mutated genes was first tested in the discovery cohort and later validated in the validation cohort. The association between specific mutated genes and tumor immunogenicity and anti-tumor immunity was further investigated in the Cancer Genome Altas (TCGA) dataset. Results Among twenty-one key genes involving in the regulation of DNA methylation, TET1-mutant (TET1-MUT) was enriched in patients responding to ICI treatment in the discovery cohort (P < 0.001). TET1 was recurrently mutated across multiple cancers and more frequently seen in skin, lung, gastrointestinal, and urogenital cancers. In the discovery cohort (n = 519), significant differences were observed between TET1-MUT and TET1-wildtype (TET1-WT) patients regarding objective response rate (ORR, 60.9% versus 22.8%, P < 0.001), durable clinical benefit (DCB, 71.4% versus 31.6%, P < 0.001), and progression-free survival (PFS, hazard ratio = 0.46 [95% confidence interval, 0.25 to 0.82], P = 0.008). In the validation cohort (n = 1395), significant overall survival (OS) benefit was detected in the TET1-MUT patients compared to TET1-WT patients (hazard ratio = 0.47 [95% confidence interval, 0.25 to 0.88], P = 0.019), which was, importantly, independent of tumor mutational burden and high microsatellite instability; as well as not attributed to the prognostic impact of TET1-MUT (P > 0.05 in both two non-ICI-treated cohorts). In TCGA dataset, TET1-MUT was strongly associated with higher tumor mutational burden and neoantigen load, and inflamed pattern of tumor-infiltrating T lymphocytes, immune signatures and immune-related gene expressions. Conclusions TET1-MUT was strongly associated with higher ORR, better DCB, longer PFS, and improved OS in patients receiving ICI treatment, suggesting that TET1-MUT is a novel predictive biomarker for immune checkpoint blockade across multiple cancer types. |
| first_indexed | 2024-12-13T14:12:26Z |
| format | Article |
| id | doaj.art-a43975f7b4e8495897296fb29ffc8742 |
| institution | Directory Open Access Journal |
| issn | 2051-1426 |
| language | English |
| last_indexed | 2024-12-13T14:12:26Z |
| publishDate | 2019-10-01 |
| publisher | BMJ Publishing Group |
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| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj.art-a43975f7b4e8495897296fb29ffc87422022-12-21T23:42:26ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262019-10-017111310.1186/s40425-019-0737-3Alteration in TET1 as potential biomarker for immune checkpoint blockade in multiple cancersHao-Xiang Wu0Yan-Xing Chen1Zi-Xian Wang2Qi Zhao3Ming-Ming He4Ying-Nan Wang5Feng Wang6Rui-Hua Xu7Department of Medical Oncology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer CenterDepartment of Medical Oncology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer CenterDepartment of Medical Oncology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer CenterDepartment of Experimental Research, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer CenterDepartment of Medical Oncology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer CenterDepartment of Medical Oncology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer CenterDepartment of Medical Oncology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer CenterDepartment of Medical Oncology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer CenterAbstract Background Immune checkpoint inhibitors (ICIs) have achieved impressive success in different cancer types, yet responses vary and predictive biomarkers are urgently needed. Growing evidence points to a link between DNA methylation and anti-tumor immunity, while clinical data on the association of genomic alterations in DNA methylation-related genes and ICI response are lacking. Methods Clinical cohorts with annotated response and survival data and matched mutational data from published studies were collected and consolidated. The predictive function of specific mutated genes was first tested in the discovery cohort and later validated in the validation cohort. The association between specific mutated genes and tumor immunogenicity and anti-tumor immunity was further investigated in the Cancer Genome Altas (TCGA) dataset. Results Among twenty-one key genes involving in the regulation of DNA methylation, TET1-mutant (TET1-MUT) was enriched in patients responding to ICI treatment in the discovery cohort (P < 0.001). TET1 was recurrently mutated across multiple cancers and more frequently seen in skin, lung, gastrointestinal, and urogenital cancers. In the discovery cohort (n = 519), significant differences were observed between TET1-MUT and TET1-wildtype (TET1-WT) patients regarding objective response rate (ORR, 60.9% versus 22.8%, P < 0.001), durable clinical benefit (DCB, 71.4% versus 31.6%, P < 0.001), and progression-free survival (PFS, hazard ratio = 0.46 [95% confidence interval, 0.25 to 0.82], P = 0.008). In the validation cohort (n = 1395), significant overall survival (OS) benefit was detected in the TET1-MUT patients compared to TET1-WT patients (hazard ratio = 0.47 [95% confidence interval, 0.25 to 0.88], P = 0.019), which was, importantly, independent of tumor mutational burden and high microsatellite instability; as well as not attributed to the prognostic impact of TET1-MUT (P > 0.05 in both two non-ICI-treated cohorts). In TCGA dataset, TET1-MUT was strongly associated with higher tumor mutational burden and neoantigen load, and inflamed pattern of tumor-infiltrating T lymphocytes, immune signatures and immune-related gene expressions. Conclusions TET1-MUT was strongly associated with higher ORR, better DCB, longer PFS, and improved OS in patients receiving ICI treatment, suggesting that TET1-MUT is a novel predictive biomarker for immune checkpoint blockade across multiple cancer types.http://link.springer.com/article/10.1186/s40425-019-0737-3BiomarkerDNA methylationImmune checkpoint blockadePan-cancerTET1 |
| spellingShingle | Hao-Xiang Wu Yan-Xing Chen Zi-Xian Wang Qi Zhao Ming-Ming He Ying-Nan Wang Feng Wang Rui-Hua Xu Alteration in TET1 as potential biomarker for immune checkpoint blockade in multiple cancers Journal for ImmunoTherapy of Cancer Biomarker DNA methylation Immune checkpoint blockade Pan-cancer TET1 |
| title | Alteration in TET1 as potential biomarker for immune checkpoint blockade in multiple cancers |
| title_full | Alteration in TET1 as potential biomarker for immune checkpoint blockade in multiple cancers |
| title_fullStr | Alteration in TET1 as potential biomarker for immune checkpoint blockade in multiple cancers |
| title_full_unstemmed | Alteration in TET1 as potential biomarker for immune checkpoint blockade in multiple cancers |
| title_short | Alteration in TET1 as potential biomarker for immune checkpoint blockade in multiple cancers |
| title_sort | alteration in tet1 as potential biomarker for immune checkpoint blockade in multiple cancers |
| topic | Biomarker DNA methylation Immune checkpoint blockade Pan-cancer TET1 |
| url | http://link.springer.com/article/10.1186/s40425-019-0737-3 |
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