STAT5 promotes PD-L1 expression by facilitating histone lactylation to drive immunosuppression in acute myeloid leukemia
Abstracts Immunotherapy is a revolutionized therapeutic strategy for tumor treatment attributing to the rapid development of genomics and immunology, and immune checkpoint inhibitors have successfully achieved responses in numbers of tumor types, including hematopoietic malignancy. However, acute my...
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2023-09-01
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| Series: | Signal Transduction and Targeted Therapy |
| Online Access: | https://doi.org/10.1038/s41392-023-01605-2 |
| _version_ | 1797556145437540352 |
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| author | Ze-Wei Huang Xue-Ning Zhang Ling Zhang Ling-Ling Liu Jing-Wen Zhang Yu-Xiang Sun Jue-Qiong Xu Quentin Liu Zi-Jie Long |
| author_facet | Ze-Wei Huang Xue-Ning Zhang Ling Zhang Ling-Ling Liu Jing-Wen Zhang Yu-Xiang Sun Jue-Qiong Xu Quentin Liu Zi-Jie Long |
| author_sort | Ze-Wei Huang |
| collection | DOAJ |
| description | Abstracts Immunotherapy is a revolutionized therapeutic strategy for tumor treatment attributing to the rapid development of genomics and immunology, and immune checkpoint inhibitors have successfully achieved responses in numbers of tumor types, including hematopoietic malignancy. However, acute myeloid leukemia (AML) is a heterogeneous disease and there is still a lack of systematic demonstration to apply immunotherapy in AML based on PD-1/PD-L1 blockage. Thus, the identification of molecules that drive tumor immunosuppression and stratify patients according to the benefit from immune checkpoint inhibitors is urgently needed. Here, we reported that STAT5 was highly expressed in the AML cohort and activated the promoter of glycolytic genes to promote glycolysis in AML cells. As a result, the increased-lactate accumulation promoted E3BP nuclear translocation and facilitated histone lactylation, ultimately inducing PD-L1 transcription. Immune checkpoint inhibitor could block the interaction of PD-1/PD-L1 and reactive CD8+ T cells in the microenvironment when co-culture with STAT5 constitutively activated AML cells. Clinically, lactate accumulation in bone marrow was positively correlated with STAT5 as well as PD-L1 expression in newly diagnosed AML patients. Therefore, we have illustrated a STAT5-lactate-PD-L1 network in AML progression, which demonstrates that AML patients with STAT5 induced-exuberant glycolysis and lactate accumulation may be benefited from PD-1/PD-L-1-based immunotherapy. |
| first_indexed | 2024-03-10T16:57:40Z |
| format | Article |
| id | doaj.art-2bb9b8ad17ca4dce91e2e77a5c77b708 |
| institution | Directory Open Access Journal |
| issn | 2059-3635 |
| language | English |
| last_indexed | 2024-03-10T16:57:40Z |
| publishDate | 2023-09-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Signal Transduction and Targeted Therapy |
| spelling | doaj.art-2bb9b8ad17ca4dce91e2e77a5c77b7082023-11-20T11:04:29ZengNature Publishing GroupSignal Transduction and Targeted Therapy2059-36352023-09-018111310.1038/s41392-023-01605-2STAT5 promotes PD-L1 expression by facilitating histone lactylation to drive immunosuppression in acute myeloid leukemiaZe-Wei Huang0Xue-Ning Zhang1Ling Zhang2Ling-Ling Liu3Jing-Wen Zhang4Yu-Xiang Sun5Jue-Qiong Xu6Quentin Liu7Zi-Jie Long8Department of Hematology, The Third Affiliated Hospital, Sun Yat-sen University; Institute of Hematology, Sun Yat-sen UniversityDepartment of Hematology, The Third Affiliated Hospital, Sun Yat-sen University; Institute of Hematology, Sun Yat-sen UniversityDepartment of Hematology, The Third Affiliated Hospital, Sun Yat-sen University; Institute of Hematology, Sun Yat-sen UniversityDepartment of Hematology, The Third Affiliated Hospital, Sun Yat-sen University; Institute of Hematology, Sun Yat-sen UniversityDepartment of Hematology, The Third Affiliated Hospital, Sun Yat-sen University; Institute of Hematology, Sun Yat-sen UniversityDepartment of Nephrology, The Third Affiliated Hospital, Sun Yat-sen UniversityDepartment of Hematology, The Third Affiliated Hospital, Sun Yat-sen University; Institute of Hematology, Sun Yat-sen UniversityDepartment of Hematology, The Third Affiliated Hospital, Sun Yat-sen University; Institute of Hematology, Sun Yat-sen UniversityDepartment of Hematology, The Third Affiliated Hospital, Sun Yat-sen University; Institute of Hematology, Sun Yat-sen UniversityAbstracts Immunotherapy is a revolutionized therapeutic strategy for tumor treatment attributing to the rapid development of genomics and immunology, and immune checkpoint inhibitors have successfully achieved responses in numbers of tumor types, including hematopoietic malignancy. However, acute myeloid leukemia (AML) is a heterogeneous disease and there is still a lack of systematic demonstration to apply immunotherapy in AML based on PD-1/PD-L1 blockage. Thus, the identification of molecules that drive tumor immunosuppression and stratify patients according to the benefit from immune checkpoint inhibitors is urgently needed. Here, we reported that STAT5 was highly expressed in the AML cohort and activated the promoter of glycolytic genes to promote glycolysis in AML cells. As a result, the increased-lactate accumulation promoted E3BP nuclear translocation and facilitated histone lactylation, ultimately inducing PD-L1 transcription. Immune checkpoint inhibitor could block the interaction of PD-1/PD-L1 and reactive CD8+ T cells in the microenvironment when co-culture with STAT5 constitutively activated AML cells. Clinically, lactate accumulation in bone marrow was positively correlated with STAT5 as well as PD-L1 expression in newly diagnosed AML patients. Therefore, we have illustrated a STAT5-lactate-PD-L1 network in AML progression, which demonstrates that AML patients with STAT5 induced-exuberant glycolysis and lactate accumulation may be benefited from PD-1/PD-L-1-based immunotherapy.https://doi.org/10.1038/s41392-023-01605-2 |
| spellingShingle | Ze-Wei Huang Xue-Ning Zhang Ling Zhang Ling-Ling Liu Jing-Wen Zhang Yu-Xiang Sun Jue-Qiong Xu Quentin Liu Zi-Jie Long STAT5 promotes PD-L1 expression by facilitating histone lactylation to drive immunosuppression in acute myeloid leukemia Signal Transduction and Targeted Therapy |
| title | STAT5 promotes PD-L1 expression by facilitating histone lactylation to drive immunosuppression in acute myeloid leukemia |
| title_full | STAT5 promotes PD-L1 expression by facilitating histone lactylation to drive immunosuppression in acute myeloid leukemia |
| title_fullStr | STAT5 promotes PD-L1 expression by facilitating histone lactylation to drive immunosuppression in acute myeloid leukemia |
| title_full_unstemmed | STAT5 promotes PD-L1 expression by facilitating histone lactylation to drive immunosuppression in acute myeloid leukemia |
| title_short | STAT5 promotes PD-L1 expression by facilitating histone lactylation to drive immunosuppression in acute myeloid leukemia |
| title_sort | stat5 promotes pd l1 expression by facilitating histone lactylation to drive immunosuppression in acute myeloid leukemia |
| url | https://doi.org/10.1038/s41392-023-01605-2 |
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