Ketoglutaric acid can reprogram the immunophenotype of triple-negative breast cancer after radiotherapy and improve the therapeutic effect of anti-PD-L1
Abstract Background Great progress has been made in applying immunotherapy to the clinical treatment of tumors. However, many patients with triple-negative breast cancer (TNBC) cannot benefit from immunotherapy due to the immune desert type of TNBC, which is unresponsive to immunotherapy. DMKG, a ce...
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| Format: | Article |
| Language: | English |
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BMC
2023-07-01
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| Series: | Journal of Translational Medicine |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s12967-023-04312-2 |
| _version_ | 1797778704297885696 |
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| author | Hongpei Tan Jiahao Liu Jing Huang Yanan Li Qiongxuan Xie Yuqian Dong Ze Mi Xiaoqian Ma Pengfei Rong |
| author_facet | Hongpei Tan Jiahao Liu Jing Huang Yanan Li Qiongxuan Xie Yuqian Dong Ze Mi Xiaoqian Ma Pengfei Rong |
| author_sort | Hongpei Tan |
| collection | DOAJ |
| description | Abstract Background Great progress has been made in applying immunotherapy to the clinical treatment of tumors. However, many patients with triple-negative breast cancer (TNBC) cannot benefit from immunotherapy due to the immune desert type of TNBC, which is unresponsive to immunotherapy. DMKG, a cell-permeable derivative of α-KG, has shown potential to address this issue. Method We investigated the effects of combining DMKG with radioimmunotherapy on TNBC. We assessed the ability of DMKG to promote tumor cell apoptosis and immunogenic death induced by radiotherapy (RT), as well as its impact on autophagy reduction, antigen and inflammatory factor release, DC cell activation, and infiltration of immune cells in the tumor area. Result Our findings indicated that DMKG significantly promoted tumor cell apoptosis and immunogenic death induced by RT. DMKG also significantly reduced autophagy in tumor cells, resulting in increased release of antigens and inflammatory factors, thereby activating DC cells. Furthermore, DMKG promoted infiltration of CD8 + T cells in the tumor area and reduced the composition of T-regulatory cells after RT, reshaping the tumor immune microenvironment. Both DMKG and RT increased the expression of PD-L1 at immune checkpoints. When combined with anti-PD-L1 drugs (α-PD-L1), they significantly inhibited tumor growth without causing obvious side effects during treatment. Conclusion Our study underscores the potential of pairing DMKG with radioimmunotherapy as an effective strategy for treating TNBC by promoting apoptosis, immunogenic death, and remodeling the tumor immune microenvironment. This combination therapy could offer a promising therapeutic avenue for TNBC patients unresponsive to conventional immunotherapy. Graphical Abstract |
| first_indexed | 2024-03-12T23:21:20Z |
| format | Article |
| id | doaj.art-69cbb2f14264449d8a703c162775fbc7 |
| institution | Directory Open Access Journal |
| issn | 1479-5876 |
| language | English |
| last_indexed | 2024-03-12T23:21:20Z |
| publishDate | 2023-07-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Translational Medicine |
| spelling | doaj.art-69cbb2f14264449d8a703c162775fbc72023-07-16T11:26:35ZengBMCJournal of Translational Medicine1479-58762023-07-0121111610.1186/s12967-023-04312-2Ketoglutaric acid can reprogram the immunophenotype of triple-negative breast cancer after radiotherapy and improve the therapeutic effect of anti-PD-L1Hongpei Tan0Jiahao Liu1Jing Huang2Yanan Li3Qiongxuan Xie4Yuqian Dong5Ze Mi6Xiaoqian Ma7Pengfei Rong8Department of Radiology, Third Xiangya Hospital, Central South UniversityDepartment of Radiology, Third Xiangya Hospital, Central South UniversityDepartment of Anesthesiology, Zhuzhou Central HospitalDepartment of Radiology, Third Xiangya Hospital, Central South UniversityDepartment of Oncology, Xiangya Hospital, Central South UniversityDepartment of Radiology, Third Xiangya Hospital, Central South UniversityDepartment of Radiology, Third Xiangya Hospital, Central South UniversityDepartment of Radiology, Third Xiangya Hospital, Central South UniversityDepartment of Radiology, Third Xiangya Hospital, Central South UniversityAbstract Background Great progress has been made in applying immunotherapy to the clinical treatment of tumors. However, many patients with triple-negative breast cancer (TNBC) cannot benefit from immunotherapy due to the immune desert type of TNBC, which is unresponsive to immunotherapy. DMKG, a cell-permeable derivative of α-KG, has shown potential to address this issue. Method We investigated the effects of combining DMKG with radioimmunotherapy on TNBC. We assessed the ability of DMKG to promote tumor cell apoptosis and immunogenic death induced by radiotherapy (RT), as well as its impact on autophagy reduction, antigen and inflammatory factor release, DC cell activation, and infiltration of immune cells in the tumor area. Result Our findings indicated that DMKG significantly promoted tumor cell apoptosis and immunogenic death induced by RT. DMKG also significantly reduced autophagy in tumor cells, resulting in increased release of antigens and inflammatory factors, thereby activating DC cells. Furthermore, DMKG promoted infiltration of CD8 + T cells in the tumor area and reduced the composition of T-regulatory cells after RT, reshaping the tumor immune microenvironment. Both DMKG and RT increased the expression of PD-L1 at immune checkpoints. When combined with anti-PD-L1 drugs (α-PD-L1), they significantly inhibited tumor growth without causing obvious side effects during treatment. Conclusion Our study underscores the potential of pairing DMKG with radioimmunotherapy as an effective strategy for treating TNBC by promoting apoptosis, immunogenic death, and remodeling the tumor immune microenvironment. This combination therapy could offer a promising therapeutic avenue for TNBC patients unresponsive to conventional immunotherapy. Graphical Abstracthttps://doi.org/10.1186/s12967-023-04312-2Ketoglutaric acidTNBCPD-L1RadiotherapyImmunogenic deathAutophagy |
| spellingShingle | Hongpei Tan Jiahao Liu Jing Huang Yanan Li Qiongxuan Xie Yuqian Dong Ze Mi Xiaoqian Ma Pengfei Rong Ketoglutaric acid can reprogram the immunophenotype of triple-negative breast cancer after radiotherapy and improve the therapeutic effect of anti-PD-L1 Journal of Translational Medicine Ketoglutaric acid TNBC PD-L1 Radiotherapy Immunogenic death Autophagy |
| title | Ketoglutaric acid can reprogram the immunophenotype of triple-negative breast cancer after radiotherapy and improve the therapeutic effect of anti-PD-L1 |
| title_full | Ketoglutaric acid can reprogram the immunophenotype of triple-negative breast cancer after radiotherapy and improve the therapeutic effect of anti-PD-L1 |
| title_fullStr | Ketoglutaric acid can reprogram the immunophenotype of triple-negative breast cancer after radiotherapy and improve the therapeutic effect of anti-PD-L1 |
| title_full_unstemmed | Ketoglutaric acid can reprogram the immunophenotype of triple-negative breast cancer after radiotherapy and improve the therapeutic effect of anti-PD-L1 |
| title_short | Ketoglutaric acid can reprogram the immunophenotype of triple-negative breast cancer after radiotherapy and improve the therapeutic effect of anti-PD-L1 |
| title_sort | ketoglutaric acid can reprogram the immunophenotype of triple negative breast cancer after radiotherapy and improve the therapeutic effect of anti pd l1 |
| topic | Ketoglutaric acid TNBC PD-L1 Radiotherapy Immunogenic death Autophagy |
| url | https://doi.org/10.1186/s12967-023-04312-2 |
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