Depletion of myeloid-derived suppressor cells sensitizes murine multiple myeloma to PD-1 checkpoint inhibitors
Background Cancer immunotherapy using immune checkpoint blockade (ICB) has revolutionized cancer treatment. However, patients with multiple myeloma (MM) rarely respond to ICB. Accumulating evidence indicates that the complicated tumor microenvironment (TME) significantly impacts the efficacy of ICB...
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BMJ Publishing Group
2025-01-01
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| Series: | Journal for ImmunoTherapy of Cancer |
| Online Access: | https://jitc.bmj.com/content/13/1/e008979.full |
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| author | Qiang Wang Qing Yi Wei Xiong Rui Duan Jianfei Qian Liuling Xiao Miao Xian Pan Su Chuanchao Zhang Yabo Li Ling Zhong Chengyun Zheng |
| author_facet | Qiang Wang Qing Yi Wei Xiong Rui Duan Jianfei Qian Liuling Xiao Miao Xian Pan Su Chuanchao Zhang Yabo Li Ling Zhong Chengyun Zheng |
| author_sort | Qiang Wang |
| collection | DOAJ |
| description | Background Cancer immunotherapy using immune checkpoint blockade (ICB) has revolutionized cancer treatment. However, patients with multiple myeloma (MM) rarely respond to ICB. Accumulating evidence indicates that the complicated tumor microenvironment (TME) significantly impacts the efficacy of ICB therapy. Therefore, investigating how TME components in MM influence ICB treatment is urgent.Methods We employed two well-established murine myeloma models, 5TGM1 and Vk*MYC, by intravenously injecting 5TGM1 or Vk*MYC cells into mice, respectively, to determine ICB therapeutic efficacy in MM. Total mouse IgG or Ig2b ELISA or QuickGel split beta SPE kits and in vivo bioluminescent imaging were used to monitor MM tumor burden. Cytometry by time of flight (CyTOF) was used to quantify MM TME components. T cell proliferation and function were detected using flow cytometry. Peptide-Fc fusion proteins were used to deplete myeloid-derived suppressor cells (MDSCs). MMDTR, Foxp3DTR, CD4 KO and CD8 KO mice were used to elucidate the underlying mechanisms. Gene expression levels in human MM were analyzed using Gene Expression Omnibus public datasets.Results We found that programmed cell death protein 1 (PD-1) antibody treatment had a therapeutic effect in 5TGM1 mice; it was ineffective in Vk*MYC mice. CyTOF indicated that the bone marrow (BM) of both models was inflamed, suggesting that immune suppressive cells might be inhibiting the reactivation of T cells in the BM. We observed higher numbers of MDSCs, regulatory T (Treg) cells, and tumor-associated macrophage (TAMs) in myeloma BM compared with that of tumor-free mice. Specifically, depleting MDSCs, but not Treg cells or TAMs, sensitized Vk*MYC mice and enhanced the response of 5TGM1 mice to PD-1 ICB, which was dependent on CD8+ but not CD4+ T cells. MDSCs, especially M-MDSCs and CD84+ MDSCs, significantly inhibited the activation and cytotoxic cytokine production of CD8+ T cells in vitro. Moreover, database profiling of patient BM revealed a negative correlation between MDSCs signature genes and cytotoxic CD8+ T cell signature genes, with post-maintenance patients with myeloma displaying a higher ratio of cytotoxic CD8+ T cell to MDSCs signature genes compared with pretreated patients.Conclusion Our study highlights the potential of MDSCs depletion in enhancing the sensitivity of patients with myeloma to PD-1 ICB therapy. |
| format | Article |
| id | doaj-art-ddc4894507f04b16a59346eec0fe3b25 |
| institution | Kabale University |
| issn | 2051-1426 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | BMJ Publishing Group |
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| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj-art-ddc4894507f04b16a59346eec0fe3b252025-01-07T17:50:08ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262025-01-0113110.1136/jitc-2024-008979Depletion of myeloid-derived suppressor cells sensitizes murine multiple myeloma to PD-1 checkpoint inhibitorsQiang Wang0Qing Yi1Wei Xiong2Rui Duan3Jianfei Qian4Liuling Xiao5Miao Xian6Pan Su7Chuanchao Zhang8Yabo Li9Ling Zhong10Chengyun Zheng11Key Laboratory of Environmental Medicine Engineering, School of Public Health, Southeast University, Nanjing, ChinaCenter for Translational Research in Hematological Malignancies, Houston Methodist Neal Cancer Center/Houston Methodist Research Institute, Houston Methodist Hospital, Houston, TX, USACenter for Translational Research in Hematologic Malignancies, Houston Methodist Neal Cancer Center, Houston Methodist Research Institute, Houston, Texas, USA2Department of Public Health Sciences, University of Miami Miller School of Medicine, Miami, Florida, USACenter for Translational Research in Hematological Malignancies, Houston Methodist Neal Cancer Center/Houston Methodist Research Institute, Houston Methodist Hospital, Houston, TX, USACenter for Translational Research in Hematological Malignancies, Houston Methodist Neal Cancer Center/Houston Methodist Research Institute, Houston Methodist Hospital, Houston, TX, USACenter for Translational Research in Hematological Malignancies, Houston Methodist Neal Cancer Center/Houston Methodist Research Institute, Houston Methodist Hospital, Houston, TX, USACenter for Translational Research in Hematological Malignancies, Houston Methodist Neal Cancer Center/Houston Methodist Research Institute, Houston Methodist Hospital, Houston, TX, USACenter for Translational Research in Hematological Malignancies, Houston Methodist Neal Cancer Center/Houston Methodist Research Institute, Houston Methodist Hospital, Houston, TX, USACenter for Translational Research in Hematological Malignancies, Houston Methodist Neal Cancer Center/Houston Methodist Research Institute, Houston Methodist Hospital, Houston, TX, USA4 Department of Research and Sponsored Programs, Children`s Minnesota Research Institute, Minneapolis, Minnesota, USADepartment of Hematology, The Second Hospital of Shandong University, Jinan, ChinaBackground Cancer immunotherapy using immune checkpoint blockade (ICB) has revolutionized cancer treatment. However, patients with multiple myeloma (MM) rarely respond to ICB. Accumulating evidence indicates that the complicated tumor microenvironment (TME) significantly impacts the efficacy of ICB therapy. Therefore, investigating how TME components in MM influence ICB treatment is urgent.Methods We employed two well-established murine myeloma models, 5TGM1 and Vk*MYC, by intravenously injecting 5TGM1 or Vk*MYC cells into mice, respectively, to determine ICB therapeutic efficacy in MM. Total mouse IgG or Ig2b ELISA or QuickGel split beta SPE kits and in vivo bioluminescent imaging were used to monitor MM tumor burden. Cytometry by time of flight (CyTOF) was used to quantify MM TME components. T cell proliferation and function were detected using flow cytometry. Peptide-Fc fusion proteins were used to deplete myeloid-derived suppressor cells (MDSCs). MMDTR, Foxp3DTR, CD4 KO and CD8 KO mice were used to elucidate the underlying mechanisms. Gene expression levels in human MM were analyzed using Gene Expression Omnibus public datasets.Results We found that programmed cell death protein 1 (PD-1) antibody treatment had a therapeutic effect in 5TGM1 mice; it was ineffective in Vk*MYC mice. CyTOF indicated that the bone marrow (BM) of both models was inflamed, suggesting that immune suppressive cells might be inhibiting the reactivation of T cells in the BM. We observed higher numbers of MDSCs, regulatory T (Treg) cells, and tumor-associated macrophage (TAMs) in myeloma BM compared with that of tumor-free mice. Specifically, depleting MDSCs, but not Treg cells or TAMs, sensitized Vk*MYC mice and enhanced the response of 5TGM1 mice to PD-1 ICB, which was dependent on CD8+ but not CD4+ T cells. MDSCs, especially M-MDSCs and CD84+ MDSCs, significantly inhibited the activation and cytotoxic cytokine production of CD8+ T cells in vitro. Moreover, database profiling of patient BM revealed a negative correlation between MDSCs signature genes and cytotoxic CD8+ T cell signature genes, with post-maintenance patients with myeloma displaying a higher ratio of cytotoxic CD8+ T cell to MDSCs signature genes compared with pretreated patients.Conclusion Our study highlights the potential of MDSCs depletion in enhancing the sensitivity of patients with myeloma to PD-1 ICB therapy.https://jitc.bmj.com/content/13/1/e008979.full |
| spellingShingle | Qiang Wang Qing Yi Wei Xiong Rui Duan Jianfei Qian Liuling Xiao Miao Xian Pan Su Chuanchao Zhang Yabo Li Ling Zhong Chengyun Zheng Depletion of myeloid-derived suppressor cells sensitizes murine multiple myeloma to PD-1 checkpoint inhibitors Journal for ImmunoTherapy of Cancer |
| title | Depletion of myeloid-derived suppressor cells sensitizes murine multiple myeloma to PD-1 checkpoint inhibitors |
| title_full | Depletion of myeloid-derived suppressor cells sensitizes murine multiple myeloma to PD-1 checkpoint inhibitors |
| title_fullStr | Depletion of myeloid-derived suppressor cells sensitizes murine multiple myeloma to PD-1 checkpoint inhibitors |
| title_full_unstemmed | Depletion of myeloid-derived suppressor cells sensitizes murine multiple myeloma to PD-1 checkpoint inhibitors |
| title_short | Depletion of myeloid-derived suppressor cells sensitizes murine multiple myeloma to PD-1 checkpoint inhibitors |
| title_sort | depletion of myeloid derived suppressor cells sensitizes murine multiple myeloma to pd 1 checkpoint inhibitors |
| url | https://jitc.bmj.com/content/13/1/e008979.full |
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