The dual role of CD70 in B‐cell lymphomagenesis
Abstract Background CD70 is a costimulatory molecule that is transiently expressed on a small set of activated lymphocytes and is involved in T‐cell‐mediated immunity. However, the role of CD70 in B‐cell malignancies remains controversial. Methods We investigated the clinical relevance of CD70 genet...
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| Format: | Article |
| Language: | English |
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Wiley
2022-12-01
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| Series: | Clinical and Translational Medicine |
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| Online Access: | https://doi.org/10.1002/ctm2.1118 |
| _version_ | 1797944077563461632 |
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| author | Man Nie Weicheng Ren Xiaofei Ye Mattias Berglund Xianhuo Wang Karin Fjordén Likun Du Yvonne Giannoula Dexin Lei Wenjia Su Wei Li Dongbing Liu Johan Linderoth Chengyi Jiang Huijing Bao Wenqi Jiang Huiqiang Huang Yong Hou Shida Zhu Gunilla Enblad Mats Jerkeman Kui Wu Huilai Zhang Rose‐Marie Amini Zhi‐Ming Li Qiang Pan‐Hammarström |
| author_facet | Man Nie Weicheng Ren Xiaofei Ye Mattias Berglund Xianhuo Wang Karin Fjordén Likun Du Yvonne Giannoula Dexin Lei Wenjia Su Wei Li Dongbing Liu Johan Linderoth Chengyi Jiang Huijing Bao Wenqi Jiang Huiqiang Huang Yong Hou Shida Zhu Gunilla Enblad Mats Jerkeman Kui Wu Huilai Zhang Rose‐Marie Amini Zhi‐Ming Li Qiang Pan‐Hammarström |
| author_sort | Man Nie |
| collection | DOAJ |
| description | Abstract Background CD70 is a costimulatory molecule that is transiently expressed on a small set of activated lymphocytes and is involved in T‐cell‐mediated immunity. However, the role of CD70 in B‐cell malignancies remains controversial. Methods We investigated the clinical relevance of CD70 genetic alterations and its protein expression in two diffuse large B‐cell lymphoma (DLBCL) cohorts with different ethnic backgrounds. We also performed transcriptomic analysis to explore the role of CD70 alterations in tumour microenvironment. We further tested the blockade of CD70 in combination with PD‐L1 inhibitor in a murine lymphoma model. Results We showed that CD70 genetic aberrations occurred more frequently in the Chinese DLBCL cohort (56/233, 24.0%) than in the Swedish cohort (9/84, 10.8%), especially in those with concomitant hepatitis B virus (HBV) infection. The CD70 genetic changes in DLBCL resulted in a reduction/loss of protein expression and/or CD27 binding, which might impair T cell priming and were independently associated with poor overall survival. Paradoxically, we observed that over‐expression of CD70 protein was also associated with a poor treatment response, as well as an advanced disease stage and EBV infection. More exhausted CD8+ T cells were furthermore identified in CD70 high‐expression DLBCLs. Finally, in a murine lymphoma model, we demonstrated that blocking the CD70/CD27 and/or PD1/PD‐L1 interactions could reduce CD70+ lymphoma growth in vivo, by directly impairing the tumour cell proliferation and rescuing the exhausted T cells. Conclusions Our findings suggest that CD70 can play a role in either tumour suppression or oncogenesis in DLBCL, likely via distinct immune evasion mechanisms, that is, impairing T cell priming or inducing T cell exhaustion. Characterisation of specific dysfunction of CD70 in DLBCL may thus provide opportunities for the development of novel targeted immuno‐therapeutic strategies. |
| first_indexed | 2024-04-10T20:33:55Z |
| format | Article |
| id | doaj.art-72a1e7b6330a448bb5e3bf510d8b3660 |
| institution | Directory Open Access Journal |
| issn | 2001-1326 |
| language | English |
| last_indexed | 2024-04-10T20:33:55Z |
| publishDate | 2022-12-01 |
| publisher | Wiley |
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| series | Clinical and Translational Medicine |
| spelling | doaj.art-72a1e7b6330a448bb5e3bf510d8b36602023-01-25T04:06:34ZengWileyClinical and Translational Medicine2001-13262022-12-011212n/an/a10.1002/ctm2.1118The dual role of CD70 in B‐cell lymphomagenesisMan Nie0Weicheng Ren1Xiaofei Ye2Mattias Berglund3Xianhuo Wang4Karin Fjordén5Likun Du6Yvonne Giannoula7Dexin Lei8Wenjia Su9Wei Li10Dongbing Liu11Johan Linderoth12Chengyi Jiang13Huijing Bao14Wenqi Jiang15Huiqiang Huang16Yong Hou17Shida Zhu18Gunilla Enblad19Mats Jerkeman20Kui Wu21Huilai Zhang22Rose‐Marie Amini23Zhi‐Ming Li24Qiang Pan‐Hammarström25Department of Medical Oncology State Key Laboratory of Oncology in South China Collaborative Innovation Center for Cancer Medicine Sun Yat‐sen University Cancer Center Guangzhou ChinaDepartment of Biosciences and Nutrition Karolinska Institutet Stockholm SwedenDepartment of Biosciences and Nutrition Karolinska Institutet Stockholm SwedenDepartment of Biosciences and Nutrition Karolinska Institutet Stockholm SwedenDepartment of Lymphoma National Clinical Research Center of Cancer Key Laboratory of Cancer Prevention and Therapy Tianjin Medical University Cancer Institute and Hospital Tianjin ChinaDepartment of Oncology Skåne University Hospital Lund SwedenDepartment of Biosciences and Nutrition Karolinska Institutet Stockholm SwedenDepartment of Biosciences and Nutrition Karolinska Institutet Stockholm SwedenDepartment of Medical Oncology State Key Laboratory of Oncology in South China Collaborative Innovation Center for Cancer Medicine Sun Yat‐sen University Cancer Center Guangzhou ChinaDepartment of Biosciences and Nutrition Karolinska Institutet Stockholm SwedenDepartment of Lymphoma National Clinical Research Center of Cancer Key Laboratory of Cancer Prevention and Therapy Tianjin Medical University Cancer Institute and Hospital Tianjin ChinaBGI‐Shenzhen Shenzhen ChinaDepartment of Oncology Skåne University Hospital Lund SwedenDepartment of Hematology Jilin Cancer Hospital Changchun ChinaDepartment of Hematology Jilin Cancer Hospital Changchun ChinaDepartment of Medical Oncology State Key Laboratory of Oncology in South China Collaborative Innovation Center for Cancer Medicine Sun Yat‐sen University Cancer Center Guangzhou ChinaDepartment of Medical Oncology State Key Laboratory of Oncology in South China Collaborative Innovation Center for Cancer Medicine Sun Yat‐sen University Cancer Center Guangzhou ChinaBGI‐Shenzhen Shenzhen ChinaBGI‐Shenzhen Shenzhen ChinaDepartment of Immunology Genetics and Pathology Uppsala University Uppsala SwedenDepartment of Oncology Skåne University Hospital Lund SwedenBGI‐Shenzhen Shenzhen ChinaDepartment of Lymphoma National Clinical Research Center of Cancer Key Laboratory of Cancer Prevention and Therapy Tianjin Medical University Cancer Institute and Hospital Tianjin ChinaDepartment of Immunology Genetics and Pathology Uppsala University Uppsala SwedenDepartment of Medical Oncology State Key Laboratory of Oncology in South China Collaborative Innovation Center for Cancer Medicine Sun Yat‐sen University Cancer Center Guangzhou ChinaDepartment of Biosciences and Nutrition Karolinska Institutet Stockholm SwedenAbstract Background CD70 is a costimulatory molecule that is transiently expressed on a small set of activated lymphocytes and is involved in T‐cell‐mediated immunity. However, the role of CD70 in B‐cell malignancies remains controversial. Methods We investigated the clinical relevance of CD70 genetic alterations and its protein expression in two diffuse large B‐cell lymphoma (DLBCL) cohorts with different ethnic backgrounds. We also performed transcriptomic analysis to explore the role of CD70 alterations in tumour microenvironment. We further tested the blockade of CD70 in combination with PD‐L1 inhibitor in a murine lymphoma model. Results We showed that CD70 genetic aberrations occurred more frequently in the Chinese DLBCL cohort (56/233, 24.0%) than in the Swedish cohort (9/84, 10.8%), especially in those with concomitant hepatitis B virus (HBV) infection. The CD70 genetic changes in DLBCL resulted in a reduction/loss of protein expression and/or CD27 binding, which might impair T cell priming and were independently associated with poor overall survival. Paradoxically, we observed that over‐expression of CD70 protein was also associated with a poor treatment response, as well as an advanced disease stage and EBV infection. More exhausted CD8+ T cells were furthermore identified in CD70 high‐expression DLBCLs. Finally, in a murine lymphoma model, we demonstrated that blocking the CD70/CD27 and/or PD1/PD‐L1 interactions could reduce CD70+ lymphoma growth in vivo, by directly impairing the tumour cell proliferation and rescuing the exhausted T cells. Conclusions Our findings suggest that CD70 can play a role in either tumour suppression or oncogenesis in DLBCL, likely via distinct immune evasion mechanisms, that is, impairing T cell priming or inducing T cell exhaustion. Characterisation of specific dysfunction of CD70 in DLBCL may thus provide opportunities for the development of novel targeted immuno‐therapeutic strategies.https://doi.org/10.1002/ctm2.1118CD70genetic aberrationdiffuse large B‐cell lymphomaimmune evasionHBV infection |
| spellingShingle | Man Nie Weicheng Ren Xiaofei Ye Mattias Berglund Xianhuo Wang Karin Fjordén Likun Du Yvonne Giannoula Dexin Lei Wenjia Su Wei Li Dongbing Liu Johan Linderoth Chengyi Jiang Huijing Bao Wenqi Jiang Huiqiang Huang Yong Hou Shida Zhu Gunilla Enblad Mats Jerkeman Kui Wu Huilai Zhang Rose‐Marie Amini Zhi‐Ming Li Qiang Pan‐Hammarström The dual role of CD70 in B‐cell lymphomagenesis Clinical and Translational Medicine CD70 genetic aberration diffuse large B‐cell lymphoma immune evasion HBV infection |
| title | The dual role of CD70 in B‐cell lymphomagenesis |
| title_full | The dual role of CD70 in B‐cell lymphomagenesis |
| title_fullStr | The dual role of CD70 in B‐cell lymphomagenesis |
| title_full_unstemmed | The dual role of CD70 in B‐cell lymphomagenesis |
| title_short | The dual role of CD70 in B‐cell lymphomagenesis |
| title_sort | dual role of cd70 in b cell lymphomagenesis |
| topic | CD70 genetic aberration diffuse large B‐cell lymphoma immune evasion HBV infection |
| url | https://doi.org/10.1002/ctm2.1118 |
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