BET bromodomain inhibition rescues PD-1-mediated T-cell exhaustion in acute myeloid leukemia
Abstract Sustained expression of programmed cell death receptor-1 (PD-1) is correlated with the exhaustion of T cells, and blockade of the PD-1 pathway is an effective immunotherapeutic strategy for treating various cancers. However, response rates are limited, and many patients do not achieve durab...
| Main Authors: | , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Nature Publishing Group
2022-08-01
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| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-022-05123-x |
| _version_ | 1811315190260563968 |
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| author | Mengjun Zhong Rili Gao Ruocong Zhao Youxue Huang Cunte Chen Kehan Li Xibao Yu Dingrui Nie Zheng Chen Xin Liu Zhuandi Liu Shaohua Chen Yuhong Lu Zhi Yu Liang Wang Peng Li Chengwu Zeng Yangqiu Li |
| author_facet | Mengjun Zhong Rili Gao Ruocong Zhao Youxue Huang Cunte Chen Kehan Li Xibao Yu Dingrui Nie Zheng Chen Xin Liu Zhuandi Liu Shaohua Chen Yuhong Lu Zhi Yu Liang Wang Peng Li Chengwu Zeng Yangqiu Li |
| author_sort | Mengjun Zhong |
| collection | DOAJ |
| description | Abstract Sustained expression of programmed cell death receptor-1 (PD-1) is correlated with the exhaustion of T cells, and blockade of the PD-1 pathway is an effective immunotherapeutic strategy for treating various cancers. However, response rates are limited, and many patients do not achieve durable responses. Thus, it is important to seek additional strategies that can improve anticancer immunity. Here, we report that the bromodomain and extraterminal domain (BET) inhibitor JQ1 inhibits PD-1 expression in Jurkat T cells, primary T cells, and T-cell exhaustion models. Furthermore, JQ1 dramatically impaired the expression of PD-1 and T-cell immunoglobulin mucin-domain-containing-3 (Tim-3) and promoted the secretion of cytokines in T cells from patients with acute myeloid leukemia (AML). In line with that, BET inhibitor-treated CD19-CAR T and CD123-CAR T cells have enhanced anti-leukemia potency and resistant to exhaustion. Mechanistically, BRD4 binds to the NFAT2 and PDCD1 (encoding PD-1) promoters, and NFAT2 binds to the PDCD1 and HAVCR2 (encoding Tim-3) promoters. JQ1-treated T cells showed downregulated NFAT2, PD-1, and Tim-3 expression. In addition, BET inhibitor suppressed programmed death-ligand 1 (PD-L1) expression and cell growth in AML cell lines and in primary AML cells. We also demonstrated that JQ1 treatment led to inhibition of leukemia progression, reduced T-cell PD-1/Tim-3 expression, and prolonged survival in MLL-AF9 AML mouse model and Nalm6 (B-cell acute lymphoblastic leukemia cell)-bearing mouse leukemia model. Taken together, BET inhibition improved anti-leukemia immunity by regulating PD-1/PD-L1 expression, and also directly suppressed AML cells, which provides novel insights on the multiple effects of BET inhibition for cancer therapy. |
| first_indexed | 2024-04-13T11:25:47Z |
| format | Article |
| id | doaj.art-c45ecc3400ef4326bb184d02bc3b711e |
| institution | Directory Open Access Journal |
| issn | 2041-4889 |
| language | English |
| last_indexed | 2024-04-13T11:25:47Z |
| publishDate | 2022-08-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj.art-c45ecc3400ef4326bb184d02bc3b711e2022-12-22T02:48:42ZengNature Publishing GroupCell Death and Disease2041-48892022-08-0113811510.1038/s41419-022-05123-xBET bromodomain inhibition rescues PD-1-mediated T-cell exhaustion in acute myeloid leukemiaMengjun Zhong0Rili Gao1Ruocong Zhao2Youxue Huang3Cunte Chen4Kehan Li5Xibao Yu6Dingrui Nie7Zheng Chen8Xin Liu9Zhuandi Liu10Shaohua Chen11Yuhong Lu12Zhi Yu13Liang Wang14Peng Li15Chengwu Zeng16Yangqiu Li17Key Laboratory for Regenerative Medicine of Ministry of Education, Institute of Hematology, Jinan UniversityKey Laboratory for Regenerative Medicine of Ministry of Education, Institute of Hematology, Jinan UniversityCenter for Cell Regeneration and Biotherapy, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of SciencesKey Laboratory for Regenerative Medicine of Ministry of Education, Institute of Hematology, Jinan UniversityKey Laboratory for Regenerative Medicine of Ministry of Education, Institute of Hematology, Jinan UniversityKey Laboratory for Regenerative Medicine of Ministry of Education, Institute of Hematology, Jinan UniversityKey Laboratory for Regenerative Medicine of Ministry of Education, Institute of Hematology, Jinan UniversityKey Laboratory for Regenerative Medicine of Ministry of Education, Institute of Hematology, Jinan UniversityKey Laboratory for Regenerative Medicine of Ministry of Education, Institute of Hematology, Jinan UniversityKey Laboratory for Regenerative Medicine of Ministry of Education, Institute of Hematology, Jinan UniversityKey Laboratory for Regenerative Medicine of Ministry of Education, Institute of Hematology, Jinan UniversityKey Laboratory for Regenerative Medicine of Ministry of Education, Institute of Hematology, Jinan UniversityDepartment of Hematology, First Affiliated Hospital, Jinan UniversityDepartment of Hematology, First Affiliated Hospital, Jinan UniversityDepartment of Oncology, First Affiliated Hospital, Jinan UniversityCenter for Cell Regeneration and Biotherapy, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of SciencesKey Laboratory for Regenerative Medicine of Ministry of Education, Institute of Hematology, Jinan UniversityKey Laboratory for Regenerative Medicine of Ministry of Education, Institute of Hematology, Jinan UniversityAbstract Sustained expression of programmed cell death receptor-1 (PD-1) is correlated with the exhaustion of T cells, and blockade of the PD-1 pathway is an effective immunotherapeutic strategy for treating various cancers. However, response rates are limited, and many patients do not achieve durable responses. Thus, it is important to seek additional strategies that can improve anticancer immunity. Here, we report that the bromodomain and extraterminal domain (BET) inhibitor JQ1 inhibits PD-1 expression in Jurkat T cells, primary T cells, and T-cell exhaustion models. Furthermore, JQ1 dramatically impaired the expression of PD-1 and T-cell immunoglobulin mucin-domain-containing-3 (Tim-3) and promoted the secretion of cytokines in T cells from patients with acute myeloid leukemia (AML). In line with that, BET inhibitor-treated CD19-CAR T and CD123-CAR T cells have enhanced anti-leukemia potency and resistant to exhaustion. Mechanistically, BRD4 binds to the NFAT2 and PDCD1 (encoding PD-1) promoters, and NFAT2 binds to the PDCD1 and HAVCR2 (encoding Tim-3) promoters. JQ1-treated T cells showed downregulated NFAT2, PD-1, and Tim-3 expression. In addition, BET inhibitor suppressed programmed death-ligand 1 (PD-L1) expression and cell growth in AML cell lines and in primary AML cells. We also demonstrated that JQ1 treatment led to inhibition of leukemia progression, reduced T-cell PD-1/Tim-3 expression, and prolonged survival in MLL-AF9 AML mouse model and Nalm6 (B-cell acute lymphoblastic leukemia cell)-bearing mouse leukemia model. Taken together, BET inhibition improved anti-leukemia immunity by regulating PD-1/PD-L1 expression, and also directly suppressed AML cells, which provides novel insights on the multiple effects of BET inhibition for cancer therapy.https://doi.org/10.1038/s41419-022-05123-x |
| spellingShingle | Mengjun Zhong Rili Gao Ruocong Zhao Youxue Huang Cunte Chen Kehan Li Xibao Yu Dingrui Nie Zheng Chen Xin Liu Zhuandi Liu Shaohua Chen Yuhong Lu Zhi Yu Liang Wang Peng Li Chengwu Zeng Yangqiu Li BET bromodomain inhibition rescues PD-1-mediated T-cell exhaustion in acute myeloid leukemia Cell Death and Disease |
| title | BET bromodomain inhibition rescues PD-1-mediated T-cell exhaustion in acute myeloid leukemia |
| title_full | BET bromodomain inhibition rescues PD-1-mediated T-cell exhaustion in acute myeloid leukemia |
| title_fullStr | BET bromodomain inhibition rescues PD-1-mediated T-cell exhaustion in acute myeloid leukemia |
| title_full_unstemmed | BET bromodomain inhibition rescues PD-1-mediated T-cell exhaustion in acute myeloid leukemia |
| title_short | BET bromodomain inhibition rescues PD-1-mediated T-cell exhaustion in acute myeloid leukemia |
| title_sort | bet bromodomain inhibition rescues pd 1 mediated t cell exhaustion in acute myeloid leukemia |
| url | https://doi.org/10.1038/s41419-022-05123-x |
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