Bacillus Calmette–Guérin Treatment Changes the Tumor Microenvironment of Non-Muscle-Invasive Bladder Cancer
BackgroundBacillus Calmette–Guérin (BCG) is currently the most effective intravesical therapy for non-muscle-invasive bladder cancer (NMIBC) as it can prevent disease recurrence and progression and lower mortality. However, the response rates to BCG vary widely and are dependent on a multitude of fa...
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| Format: | Article |
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Frontiers Media S.A.
2022-03-01
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| Series: | Frontiers in Oncology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fonc.2022.842182/full |
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| author | Fei Su Ming Liu Wei Zhang Min Tang Jinsong Zhang Hexin Li Lihui Zou Rui Zhang Yudong Liu Lin Li Jie Ma Jie Ma Yaqun Zhang Meng Chen Fei Xiao Fei Xiao |
| author_facet | Fei Su Ming Liu Wei Zhang Min Tang Jinsong Zhang Hexin Li Lihui Zou Rui Zhang Yudong Liu Lin Li Jie Ma Jie Ma Yaqun Zhang Meng Chen Fei Xiao Fei Xiao |
| author_sort | Fei Su |
| collection | DOAJ |
| description | BackgroundBacillus Calmette–Guérin (BCG) is currently the most effective intravesical therapy for non-muscle-invasive bladder cancer (NMIBC) as it can prevent disease recurrence and progression and lower mortality. However, the response rates to BCG vary widely and are dependent on a multitude of factors.MethodsWe performed a systematic discovery by analyzing the whole exome sequence, expression profile, and immune repertoire sequence of treatment-naive and 5-year time-serial relapsed tumors from 24 NMIBC patients.ResultsBCG therapy showed bidirectional effects on tumor evolution and immune checkpoint landscape, along with a significant reduction of the percentage of neoantigen burden. In addition, a remarkable proportion of subclonal mutations were unique to the matched pre- or post-treatment tumors, suggesting the presence of BCG-induced and/or spatial heterogeneity. In the relapsed tumors, we identified and validated a shift in the mutational signatures in which mutations associated with aristolochic acid (AA) exposure were enriched, implying AA may be associated with tumor recurrence. Enhanced expressions of immune checkpoint regulation genes were found in the relapsed tumors, suggesting that the combination of immune checkpoint with BCG treatment may be an effective strategy to treat NMIBC. TCR sequencing revealed treatment-associated changes in the T-cell repertoire in the primary and relapsed tumors.ConclusionOur results provide insight into the genomic and immune dynamics of tumor evolution with BCG treatment, suggest new mechanisms of BCG resistance, and inform the development of clinically relevant biomarkers and trials of potential immune checkpoint inhibitor combination therapies. |
| first_indexed | 2024-12-10T17:07:53Z |
| format | Article |
| id | doaj.art-e0c813ceaa764766b85770f0bbc408be |
| institution | Directory Open Access Journal |
| issn | 2234-943X |
| language | English |
| last_indexed | 2024-12-10T17:07:53Z |
| publishDate | 2022-03-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Oncology |
| spelling | doaj.art-e0c813ceaa764766b85770f0bbc408be2022-12-22T01:40:24ZengFrontiers Media S.A.Frontiers in Oncology2234-943X2022-03-011210.3389/fonc.2022.842182842182Bacillus Calmette–Guérin Treatment Changes the Tumor Microenvironment of Non-Muscle-Invasive Bladder CancerFei Su0Ming Liu1Wei Zhang2Min Tang3Jinsong Zhang4Hexin Li5Lihui Zou6Rui Zhang7Yudong Liu8Lin Li9Jie Ma10Jie Ma11Yaqun Zhang12Meng Chen13Fei Xiao14Fei Xiao15Clinical Biobank, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, ChinaDepartment of Urology, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, ChinaDepartment of Pathology, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, ChinaDepartment of Oncology, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, ChinaDepartment of Pathology, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, ChinaClinical Biobank, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, ChinaThe Key Laboratory of Geriatrics, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, ChinaNational Center for Clinical Laboratories, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, ChinaThe Key Laboratory of Geriatrics, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, ChinaDepartment of Oncology, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, ChinaCenter for Biotherapy, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, ChinaState Key Lab of Molecular Oncology, National Cancer Center, Chinese Academy of Medical Sciences Cancer Hospital & Peking Union Medical College, Beijing, ChinaDepartment of Urology, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, ChinaNational Cancer Data Center, National Cancer Center, Chinese Academy of Medical Sciences Cancer Hospital & Peking Union Medical College, Beijing, ChinaClinical Biobank, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, ChinaThe Key Laboratory of Geriatrics, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, ChinaBackgroundBacillus Calmette–Guérin (BCG) is currently the most effective intravesical therapy for non-muscle-invasive bladder cancer (NMIBC) as it can prevent disease recurrence and progression and lower mortality. However, the response rates to BCG vary widely and are dependent on a multitude of factors.MethodsWe performed a systematic discovery by analyzing the whole exome sequence, expression profile, and immune repertoire sequence of treatment-naive and 5-year time-serial relapsed tumors from 24 NMIBC patients.ResultsBCG therapy showed bidirectional effects on tumor evolution and immune checkpoint landscape, along with a significant reduction of the percentage of neoantigen burden. In addition, a remarkable proportion of subclonal mutations were unique to the matched pre- or post-treatment tumors, suggesting the presence of BCG-induced and/or spatial heterogeneity. In the relapsed tumors, we identified and validated a shift in the mutational signatures in which mutations associated with aristolochic acid (AA) exposure were enriched, implying AA may be associated with tumor recurrence. Enhanced expressions of immune checkpoint regulation genes were found in the relapsed tumors, suggesting that the combination of immune checkpoint with BCG treatment may be an effective strategy to treat NMIBC. TCR sequencing revealed treatment-associated changes in the T-cell repertoire in the primary and relapsed tumors.ConclusionOur results provide insight into the genomic and immune dynamics of tumor evolution with BCG treatment, suggest new mechanisms of BCG resistance, and inform the development of clinically relevant biomarkers and trials of potential immune checkpoint inhibitor combination therapies.https://www.frontiersin.org/articles/10.3389/fonc.2022.842182/fullBacillus Calmette–Guérinnon-muscle-invasive bladder cancerimmune checkpointtumor microenvironmentneoantigen |
| spellingShingle | Fei Su Ming Liu Wei Zhang Min Tang Jinsong Zhang Hexin Li Lihui Zou Rui Zhang Yudong Liu Lin Li Jie Ma Jie Ma Yaqun Zhang Meng Chen Fei Xiao Fei Xiao Bacillus Calmette–Guérin Treatment Changes the Tumor Microenvironment of Non-Muscle-Invasive Bladder Cancer Frontiers in Oncology Bacillus Calmette–Guérin non-muscle-invasive bladder cancer immune checkpoint tumor microenvironment neoantigen |
| title | Bacillus Calmette–Guérin Treatment Changes the Tumor Microenvironment of Non-Muscle-Invasive Bladder Cancer |
| title_full | Bacillus Calmette–Guérin Treatment Changes the Tumor Microenvironment of Non-Muscle-Invasive Bladder Cancer |
| title_fullStr | Bacillus Calmette–Guérin Treatment Changes the Tumor Microenvironment of Non-Muscle-Invasive Bladder Cancer |
| title_full_unstemmed | Bacillus Calmette–Guérin Treatment Changes the Tumor Microenvironment of Non-Muscle-Invasive Bladder Cancer |
| title_short | Bacillus Calmette–Guérin Treatment Changes the Tumor Microenvironment of Non-Muscle-Invasive Bladder Cancer |
| title_sort | bacillus calmette guerin treatment changes the tumor microenvironment of non muscle invasive bladder cancer |
| topic | Bacillus Calmette–Guérin non-muscle-invasive bladder cancer immune checkpoint tumor microenvironment neoantigen |
| url | https://www.frontiersin.org/articles/10.3389/fonc.2022.842182/full |
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