Allogeneic DNT cell therapy synergizes with T cells to promote anti-leukemic activities while suppressing GvHD
Abstract Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a second-line treatment with curative potential for leukemia patients. However, the prognosis of allo-HSCT patients with disease relapse or graft-versus-host disease (GvHD) is poor. CD4+ or CD8+ conventional T (Tconv) cells a...
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| Format: | Article |
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BMC
2025-01-01
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| Series: | Journal of Experimental & Clinical Cancer Research |
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| Online Access: | https://doi.org/10.1186/s13046-024-03247-w |
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| author | Jongbok Lee Hyeonjeong Kang Branson Chen Yoosu Na Ismat Khatri Fraser Soares Housheng Hansen He Arjun D. Law Tianzhong Pan Armin Gerbitz Xiaoyu Zhu Mark D. Minden Li Zhang |
| author_facet | Jongbok Lee Hyeonjeong Kang Branson Chen Yoosu Na Ismat Khatri Fraser Soares Housheng Hansen He Arjun D. Law Tianzhong Pan Armin Gerbitz Xiaoyu Zhu Mark D. Minden Li Zhang |
| author_sort | Jongbok Lee |
| collection | DOAJ |
| description | Abstract Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a second-line treatment with curative potential for leukemia patients. However, the prognosis of allo-HSCT patients with disease relapse or graft-versus-host disease (GvHD) is poor. CD4+ or CD8+ conventional T (Tconv) cells are critically involved in mediating anti-leukemic immune responses to prevent relapse and detrimental GvHD. Hence, treatment for one increases the risk of the other. Thus, therapeutic strategies that can address relapse and GvHD are considered the Holy Grail of allo-HSCT. CD3+CD4−CD8− double-negative T cells (DNTs) are unconventional mature T cells with potent anti-leukemia effects with “off-the-shelf” potential. A phase I clinical trial demonstrated the feasibility, safety, and potential efficacy of allogeneic DNT therapy for patients with relapsing acute myeloid leukemia (AML) post-allo-HSCT. Here, we studied the impact of DNTs on the anti-leukemic and GvHD-inducing activities of Tconv cells. DNTs synergized with Tconv cells to mediate superior anti-leukemic activity. Mechanistically, DNTs released soluble factors which activated and evoked potent anti-leukemic activities of Tconv cells. In contrast, DNTs suppressed GvHD-inducing activities of Tconv cells in a CD18-dependent manner by mediating cytotoxicity against proliferative Tconv cells. The seemingly opposite immunological activities of DNTs were dictated by the presence or absence of AML cells. Collectively, these results support the potential of DNTs as an adjuvant to allo-HSCT to address both disease relapse and GvHD. |
| format | Article |
| id | doaj-art-22bb27badd3244598e43619bd1da6170 |
| institution | Kabale University |
| issn | 1756-9966 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Experimental & Clinical Cancer Research |
| spelling | doaj-art-22bb27badd3244598e43619bd1da61702025-02-02T12:47:50ZengBMCJournal of Experimental & Clinical Cancer Research1756-99662025-01-0144111910.1186/s13046-024-03247-wAllogeneic DNT cell therapy synergizes with T cells to promote anti-leukemic activities while suppressing GvHDJongbok Lee0Hyeonjeong Kang1Branson Chen2Yoosu Na3Ismat Khatri4Fraser Soares5Housheng Hansen He6Arjun D. Law7Tianzhong Pan8Armin Gerbitz9Xiaoyu Zhu10Mark D. Minden11Li Zhang12Toronto General Hospital Research Institute, University Health NetworkToronto General Hospital Research Institute, University Health NetworkToronto General Hospital Research Institute, University Health NetworkToronto General Hospital Research Institute, University Health NetworkToronto General Hospital Research Institute, University Health NetworkPrincess Margaret Cancer Centre, University Health NetworkPrincess Margaret Cancer Centre, University Health NetworkPrincess Margaret Cancer Centre, University Health NetworkDepartment of Hematology, the First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of ChinaPrincess Margaret Cancer Centre, University Health NetworkDepartment of Hematology, the First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of ChinaPrincess Margaret Cancer Centre, University Health NetworkToronto General Hospital Research Institute, University Health NetworkAbstract Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a second-line treatment with curative potential for leukemia patients. However, the prognosis of allo-HSCT patients with disease relapse or graft-versus-host disease (GvHD) is poor. CD4+ or CD8+ conventional T (Tconv) cells are critically involved in mediating anti-leukemic immune responses to prevent relapse and detrimental GvHD. Hence, treatment for one increases the risk of the other. Thus, therapeutic strategies that can address relapse and GvHD are considered the Holy Grail of allo-HSCT. CD3+CD4−CD8− double-negative T cells (DNTs) are unconventional mature T cells with potent anti-leukemia effects with “off-the-shelf” potential. A phase I clinical trial demonstrated the feasibility, safety, and potential efficacy of allogeneic DNT therapy for patients with relapsing acute myeloid leukemia (AML) post-allo-HSCT. Here, we studied the impact of DNTs on the anti-leukemic and GvHD-inducing activities of Tconv cells. DNTs synergized with Tconv cells to mediate superior anti-leukemic activity. Mechanistically, DNTs released soluble factors which activated and evoked potent anti-leukemic activities of Tconv cells. In contrast, DNTs suppressed GvHD-inducing activities of Tconv cells in a CD18-dependent manner by mediating cytotoxicity against proliferative Tconv cells. The seemingly opposite immunological activities of DNTs were dictated by the presence or absence of AML cells. Collectively, these results support the potential of DNTs as an adjuvant to allo-HSCT to address both disease relapse and GvHD.https://doi.org/10.1186/s13046-024-03247-wDouble negative T cellAllogeneic hematopoietic stem cell transplantationGraft-versus-host diseaseGraft-versus-leukemiaDonor lymphocyte infusion |
| spellingShingle | Jongbok Lee Hyeonjeong Kang Branson Chen Yoosu Na Ismat Khatri Fraser Soares Housheng Hansen He Arjun D. Law Tianzhong Pan Armin Gerbitz Xiaoyu Zhu Mark D. Minden Li Zhang Allogeneic DNT cell therapy synergizes with T cells to promote anti-leukemic activities while suppressing GvHD Journal of Experimental & Clinical Cancer Research Double negative T cell Allogeneic hematopoietic stem cell transplantation Graft-versus-host disease Graft-versus-leukemia Donor lymphocyte infusion |
| title | Allogeneic DNT cell therapy synergizes with T cells to promote anti-leukemic activities while suppressing GvHD |
| title_full | Allogeneic DNT cell therapy synergizes with T cells to promote anti-leukemic activities while suppressing GvHD |
| title_fullStr | Allogeneic DNT cell therapy synergizes with T cells to promote anti-leukemic activities while suppressing GvHD |
| title_full_unstemmed | Allogeneic DNT cell therapy synergizes with T cells to promote anti-leukemic activities while suppressing GvHD |
| title_short | Allogeneic DNT cell therapy synergizes with T cells to promote anti-leukemic activities while suppressing GvHD |
| title_sort | allogeneic dnt cell therapy synergizes with t cells to promote anti leukemic activities while suppressing gvhd |
| topic | Double negative T cell Allogeneic hematopoietic stem cell transplantation Graft-versus-host disease Graft-versus-leukemia Donor lymphocyte infusion |
| url | https://doi.org/10.1186/s13046-024-03247-w |
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