Polyfunctional CD8+CD226+RUNX2hi effector T cells are diminished in advanced stages of chronic lymphocytic leukemia
CD8+ T cells, a subset of T cells identified by the surface glycoprotein CD8, particularly those expressing the co‐stimulatory molecule CD226, play a crucial role in the immune response to malignancies. However, their role in chronic lymphocytic leukemia (CLL), an immunosuppressive disease, has not...
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| Format: | Article |
| Language: | English |
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Wiley
2025-05-01
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| Series: | Molecular Oncology |
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| Online Access: | https://doi.org/10.1002/1878-0261.13793 |
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| author | Maryam Rezaeifar Shima Shahbaz Anthea C. Peters Spencer B. Gibson Shokrollah Elahi |
| author_facet | Maryam Rezaeifar Shima Shahbaz Anthea C. Peters Spencer B. Gibson Shokrollah Elahi |
| author_sort | Maryam Rezaeifar |
| collection | DOAJ |
| description | CD8+ T cells, a subset of T cells identified by the surface glycoprotein CD8, particularly those expressing the co‐stimulatory molecule CD226, play a crucial role in the immune response to malignancies. However, their role in chronic lymphocytic leukemia (CLL), an immunosuppressive disease, has not yet been explored. We studied 64 CLL patients and 25 age‐ and sex‐matched healthy controls (HCs). We analyzed the proportion of CD226‐expressing cells among different CD8+ T cell subsets (including naïve, central memory, effector memory, and effectors) in CLL patients, stratified by Rai stage and immunoglobulin heavy‐chain variable region gene (IgHV) mutation status. Additionally, we compared the effector functions of CD8+CD226+ cells and their CD226− counterparts. We also quantified cytokine and chemokine levels in the plasma of CLL and HCs. Furthermore, we reanalyzed the publicly available bulk RNA‐seq on CD226+ and CD226−CD8+ T cells. Finally, we evaluated the impact of elevated cytokines/chemokines on CD226 expression. Our results showed that CD226‐expressing cells were significantly decreased within the effector memory and effector CD8+ T cell subsets in CLL patients with advanced Rai stages and unmutated IgHV, a marker of poor prognosis. These cells displayed robust effector functions, including cytokine production, cytolytic activity, degranulation, proliferation, and migration capacity. In contrast, CD8+CD226− T cells displayed an exhausted phenotype with reduced Runt‐related transcription factor 2 (RUNX2) expression. Elevated levels of interleukin‐6 (IL‐6) and macrophage inflammatory protein‐1 beta (MIP‐1β) were inversely correlated with the frequency of CD8+CD226+ T cells and may contribute to the downregulation of CD226, possibly leading to T cell dysfunction in CLL. Our findings highlight the critical role of CD8+CD226+RUNX2hi T cells in CLL and suggest that their reduction is associated with disease progression and poor clinical outcomes. This study also underscores the potential of targeting IL‐6 and MIP‐1β to preserve polyfunctional CD8+CD226+ T cells as a promising immunotherapy strategy. |
| format | Article |
| id | doaj-art-a6565ed0d7e149b78bb9cff34dda5ad1 |
| institution | DOAJ |
| issn | 1574-7891 1878-0261 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | Wiley |
| record_format | Article |
| series | Molecular Oncology |
| spelling | doaj-art-a6565ed0d7e149b78bb9cff34dda5ad12025-08-20T02:58:55ZengWileyMolecular Oncology1574-78911878-02612025-05-011951347137010.1002/1878-0261.13793Polyfunctional CD8+CD226+RUNX2hi effector T cells are diminished in advanced stages of chronic lymphocytic leukemiaMaryam Rezaeifar0Shima Shahbaz1Anthea C. Peters2Spencer B. Gibson3Shokrollah Elahi4Division of Foundational Sciences, Mike Petryk School of Dentistry University of Alberta Edmonton CanadaDivision of Foundational Sciences, Mike Petryk School of Dentistry University of Alberta Edmonton CanadaDivision of Medical Oncology, Department of Oncology University of Alberta Edmonton CanadaDivision of Medical Oncology, Department of Oncology University of Alberta Edmonton CanadaDivision of Foundational Sciences, Mike Petryk School of Dentistry University of Alberta Edmonton CanadaCD8+ T cells, a subset of T cells identified by the surface glycoprotein CD8, particularly those expressing the co‐stimulatory molecule CD226, play a crucial role in the immune response to malignancies. However, their role in chronic lymphocytic leukemia (CLL), an immunosuppressive disease, has not yet been explored. We studied 64 CLL patients and 25 age‐ and sex‐matched healthy controls (HCs). We analyzed the proportion of CD226‐expressing cells among different CD8+ T cell subsets (including naïve, central memory, effector memory, and effectors) in CLL patients, stratified by Rai stage and immunoglobulin heavy‐chain variable region gene (IgHV) mutation status. Additionally, we compared the effector functions of CD8+CD226+ cells and their CD226− counterparts. We also quantified cytokine and chemokine levels in the plasma of CLL and HCs. Furthermore, we reanalyzed the publicly available bulk RNA‐seq on CD226+ and CD226−CD8+ T cells. Finally, we evaluated the impact of elevated cytokines/chemokines on CD226 expression. Our results showed that CD226‐expressing cells were significantly decreased within the effector memory and effector CD8+ T cell subsets in CLL patients with advanced Rai stages and unmutated IgHV, a marker of poor prognosis. These cells displayed robust effector functions, including cytokine production, cytolytic activity, degranulation, proliferation, and migration capacity. In contrast, CD8+CD226− T cells displayed an exhausted phenotype with reduced Runt‐related transcription factor 2 (RUNX2) expression. Elevated levels of interleukin‐6 (IL‐6) and macrophage inflammatory protein‐1 beta (MIP‐1β) were inversely correlated with the frequency of CD8+CD226+ T cells and may contribute to the downregulation of CD226, possibly leading to T cell dysfunction in CLL. Our findings highlight the critical role of CD8+CD226+RUNX2hi T cells in CLL and suggest that their reduction is associated with disease progression and poor clinical outcomes. This study also underscores the potential of targeting IL‐6 and MIP‐1β to preserve polyfunctional CD8+CD226+ T cells as a promising immunotherapy strategy.https://doi.org/10.1002/1878-0261.13793CD29+ T cellco‐inhibitory receptorsIL‐6 and MIP‐1βNK‐T cell‐like |
| spellingShingle | Maryam Rezaeifar Shima Shahbaz Anthea C. Peters Spencer B. Gibson Shokrollah Elahi Polyfunctional CD8+CD226+RUNX2hi effector T cells are diminished in advanced stages of chronic lymphocytic leukemia Molecular Oncology CD29+ T cell co‐inhibitory receptors IL‐6 and MIP‐1β NK‐T cell‐like |
| title | Polyfunctional CD8+CD226+RUNX2hi effector T cells are diminished in advanced stages of chronic lymphocytic leukemia |
| title_full | Polyfunctional CD8+CD226+RUNX2hi effector T cells are diminished in advanced stages of chronic lymphocytic leukemia |
| title_fullStr | Polyfunctional CD8+CD226+RUNX2hi effector T cells are diminished in advanced stages of chronic lymphocytic leukemia |
| title_full_unstemmed | Polyfunctional CD8+CD226+RUNX2hi effector T cells are diminished in advanced stages of chronic lymphocytic leukemia |
| title_short | Polyfunctional CD8+CD226+RUNX2hi effector T cells are diminished in advanced stages of chronic lymphocytic leukemia |
| title_sort | polyfunctional cd8 cd226 runx2hi effector t cells are diminished in advanced stages of chronic lymphocytic leukemia |
| topic | CD29+ T cell co‐inhibitory receptors IL‐6 and MIP‐1β NK‐T cell‐like |
| url | https://doi.org/10.1002/1878-0261.13793 |
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