Genetic Mutations of Tim-3 Ligand and Exhausted Tim-3+ CD8+ T Cells and Survival in Diffuse Large B Cell Lymphoma
Tim-3 is a promising target for antitumor immunotherapy. A number of clinical trials are evaluating the efficacy of anti-Tim-3 therapies as a single agent or combinations in solid tumors and haematologic malignancies. However, there remains a considerable lack of data on Tim-3 signalling, especially...
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| Format: | Article |
| Language: | English |
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Wiley
2020-01-01
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| Series: | Journal of Immunology Research |
| Online Access: | http://dx.doi.org/10.1155/2020/6968595 |
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| author | Tingting Zhang Tianyuan Ren Zheng Song Jing Zhao Lei Jiao Zhenzhen Zhang Jin He Xianming Liu Lihua Qiu Lanfang Li Shiyong Zhou Bin Meng Qiongli Zhai Xiubao Ren Zhengzi Qian Xianhuo Wang Huilai Zhang |
| author_facet | Tingting Zhang Tianyuan Ren Zheng Song Jing Zhao Lei Jiao Zhenzhen Zhang Jin He Xianming Liu Lihua Qiu Lanfang Li Shiyong Zhou Bin Meng Qiongli Zhai Xiubao Ren Zhengzi Qian Xianhuo Wang Huilai Zhang |
| author_sort | Tingting Zhang |
| collection | DOAJ |
| description | Tim-3 is a promising target for antitumor immunotherapy. A number of clinical trials are evaluating the efficacy of anti-Tim-3 therapies as a single agent or combinations in solid tumors and haematologic malignancies. However, there remains a considerable lack of data on Tim-3 signalling, especially the genetic characteristics and immune microenvironment, in diffuse large B cell lymphoma (DLBCL). Herein, we identified three genetic mutations in galectin-9, a major ligand of Tim-3, in six patients with DLBCL (6/188, 3.2%) that were not detected in the COSMIC database. The Oncomine database showed that the mRNA levels of Tim-3 were higher in DLBCL cells than those in normal B cells. Multiplexed immunofluorescence revealed that patients with Tim-3-expressing tumor-infiltrating lymphocytes (Tim-3+ TILs) exhibited poor outcomes than those with Tim-3- TILs (p=0.041). The median survival times of these patients were 65.0 (95% confidence interval (CI): 71.2–88.6) and 79.9 months (95% CI: 54.4–75.6), respectively. Furthermore, we defined a novel subtype of exhausted T cells, named as exhausted Tim-3+ CD8+ T cells, and found that patients with exhausted Tim-3+ CD8+ T cells (median survival, 62.8 months, 95% CI: 50.0–75.6) exhibited shorter survival than those with nonexhausted Tim-3- CD8+ T cells (median survival, 82.5 months, 95% CI: 72.0–92.9; p=0.034). Overall, these findings provide the genetic status of the Tim-3 ligand in DLBCL. Patients with Tim-3+ TILs and exhausted Tim-3+ CD8+ T cells exhibited inferior survival, thus highlighting the possibility of potential therapeutic applications of the inhibition of Tim-3 alone or in combination with other immune checkpoints for treatment of patients with DLBCL. |
| format | Article |
| id | doaj-art-309362fdb2364a449f05d158d9f6452d |
| institution | Kabale University |
| issn | 2314-8861 2314-7156 |
| language | English |
| publishDate | 2020-01-01 |
| publisher | Wiley |
| record_format | Article |
| series | Journal of Immunology Research |
| spelling | doaj-art-309362fdb2364a449f05d158d9f6452d2025-02-03T05:52:34ZengWileyJournal of Immunology Research2314-88612314-71562020-01-01202010.1155/2020/69685956968595Genetic Mutations of Tim-3 Ligand and Exhausted Tim-3+ CD8+ T Cells and Survival in Diffuse Large B Cell LymphomaTingting Zhang0Tianyuan Ren1Zheng Song2Jing Zhao3Lei Jiao4Zhenzhen Zhang5Jin He6Xianming Liu7Lihua Qiu8Lanfang Li9Shiyong Zhou10Bin Meng11Qiongli Zhai12Xiubao Ren13Zhengzi Qian14Xianhuo Wang15Huilai Zhang16Department of Lymphoma, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin’s Clinical Research Center for Cancer, The Sino-US Center for Lymphoma and Leukemia Research, Tianjin, ChinaDepartment of Lymphoma, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin’s Clinical Research Center for Cancer, The Sino-US Center for Lymphoma and Leukemia Research, Tianjin, ChinaDepartment of Lymphoma, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin’s Clinical Research Center for Cancer, The Sino-US Center for Lymphoma and Leukemia Research, Tianjin, ChinaDepartment of Lymphoma, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin’s Clinical Research Center for Cancer, The Sino-US Center for Lymphoma and Leukemia Research, Tianjin, ChinaPanovue Biological Technology Co., Ltd., Beijing, ChinaMarvel Medical Laboratory, Tianjin Marvelbio Technology Co. Ltd., Tianjin, ChinaDepartment of Lymphoma, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin’s Clinical Research Center for Cancer, The Sino-US Center for Lymphoma and Leukemia Research, Tianjin, ChinaDepartment of Lymphoma, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin’s Clinical Research Center for Cancer, The Sino-US Center for Lymphoma and Leukemia Research, Tianjin, ChinaDepartment of Lymphoma, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin’s Clinical Research Center for Cancer, The Sino-US Center for Lymphoma and Leukemia Research, Tianjin, ChinaDepartment of Lymphoma, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin’s Clinical Research Center for Cancer, The Sino-US Center for Lymphoma and Leukemia Research, Tianjin, ChinaDepartment of Lymphoma, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin’s Clinical Research Center for Cancer, The Sino-US Center for Lymphoma and Leukemia Research, Tianjin, ChinaDepartment of Pathology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, ChinaDepartment of Pathology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, ChinaDepartment of Immunology/Biotherapy, Tianjin Medical University Cancer Institute and Hospital, Tianjin, ChinaDepartment of Lymphoma, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin’s Clinical Research Center for Cancer, The Sino-US Center for Lymphoma and Leukemia Research, Tianjin, ChinaDepartment of Lymphoma, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin’s Clinical Research Center for Cancer, The Sino-US Center for Lymphoma and Leukemia Research, Tianjin, ChinaDepartment of Lymphoma, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin’s Clinical Research Center for Cancer, The Sino-US Center for Lymphoma and Leukemia Research, Tianjin, ChinaTim-3 is a promising target for antitumor immunotherapy. A number of clinical trials are evaluating the efficacy of anti-Tim-3 therapies as a single agent or combinations in solid tumors and haematologic malignancies. However, there remains a considerable lack of data on Tim-3 signalling, especially the genetic characteristics and immune microenvironment, in diffuse large B cell lymphoma (DLBCL). Herein, we identified three genetic mutations in galectin-9, a major ligand of Tim-3, in six patients with DLBCL (6/188, 3.2%) that were not detected in the COSMIC database. The Oncomine database showed that the mRNA levels of Tim-3 were higher in DLBCL cells than those in normal B cells. Multiplexed immunofluorescence revealed that patients with Tim-3-expressing tumor-infiltrating lymphocytes (Tim-3+ TILs) exhibited poor outcomes than those with Tim-3- TILs (p=0.041). The median survival times of these patients were 65.0 (95% confidence interval (CI): 71.2–88.6) and 79.9 months (95% CI: 54.4–75.6), respectively. Furthermore, we defined a novel subtype of exhausted T cells, named as exhausted Tim-3+ CD8+ T cells, and found that patients with exhausted Tim-3+ CD8+ T cells (median survival, 62.8 months, 95% CI: 50.0–75.6) exhibited shorter survival than those with nonexhausted Tim-3- CD8+ T cells (median survival, 82.5 months, 95% CI: 72.0–92.9; p=0.034). Overall, these findings provide the genetic status of the Tim-3 ligand in DLBCL. Patients with Tim-3+ TILs and exhausted Tim-3+ CD8+ T cells exhibited inferior survival, thus highlighting the possibility of potential therapeutic applications of the inhibition of Tim-3 alone or in combination with other immune checkpoints for treatment of patients with DLBCL.http://dx.doi.org/10.1155/2020/6968595 |
| spellingShingle | Tingting Zhang Tianyuan Ren Zheng Song Jing Zhao Lei Jiao Zhenzhen Zhang Jin He Xianming Liu Lihua Qiu Lanfang Li Shiyong Zhou Bin Meng Qiongli Zhai Xiubao Ren Zhengzi Qian Xianhuo Wang Huilai Zhang Genetic Mutations of Tim-3 Ligand and Exhausted Tim-3+ CD8+ T Cells and Survival in Diffuse Large B Cell Lymphoma Journal of Immunology Research |
| title | Genetic Mutations of Tim-3 Ligand and Exhausted Tim-3+ CD8+ T Cells and Survival in Diffuse Large B Cell Lymphoma |
| title_full | Genetic Mutations of Tim-3 Ligand and Exhausted Tim-3+ CD8+ T Cells and Survival in Diffuse Large B Cell Lymphoma |
| title_fullStr | Genetic Mutations of Tim-3 Ligand and Exhausted Tim-3+ CD8+ T Cells and Survival in Diffuse Large B Cell Lymphoma |
| title_full_unstemmed | Genetic Mutations of Tim-3 Ligand and Exhausted Tim-3+ CD8+ T Cells and Survival in Diffuse Large B Cell Lymphoma |
| title_short | Genetic Mutations of Tim-3 Ligand and Exhausted Tim-3+ CD8+ T Cells and Survival in Diffuse Large B Cell Lymphoma |
| title_sort | genetic mutations of tim 3 ligand and exhausted tim 3 cd8 t cells and survival in diffuse large b cell lymphoma |
| url | http://dx.doi.org/10.1155/2020/6968595 |
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