{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,20]],"date-time":"2026-09-20T12:24:09Z","timestamp":1789907049732,"version":"4.0.1"},"reference-count":106,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2025,1,7]],"date-time":"2025-01-07T00:00:00Z","timestamp":1736208000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100009326","name":"Cancer Research Society","doi-asserted-by":"publisher","award":["945992"],"award-info":[{"award-number":["945992"]}],"id":[{"id":"10.13039\/100009326","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["febs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Molecular Oncology"],"published-print":{"date-parts":[[2025,5]]},"abstract":"<jats:p>\n                    CD8\n                    <jats:sup>+<\/jats:sup>\n                    T\u00a0cells, a subset of T\u00a0cells identified by the surface glycoprotein CD8, particularly those expressing the co\u2010stimulatory 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\u2010 and sex\u2010matched healthy controls (HCs). We analyzed the proportion of CD226\u2010expressing cells among different CD8\n                    <jats:sup>+<\/jats:sup>\n                    T\u00a0cell subsets (including na\u00efve, central memory, effector memory, and effectors) in CLL patients, stratified by Rai stage and immunoglobulin heavy\u2010chain variable region gene (IgHV) mutation status. Additionally, we compared the effector functions of CD8\n                    <jats:sup>+<\/jats:sup>\n                    CD226\n                    <jats:sup>+<\/jats:sup>\n                    cells and their CD226\n                    <jats:sup>\u2212<\/jats:sup>\n                    counterparts. We also quantified cytokine and chemokine levels in the plasma of CLL and HCs. Furthermore, we reanalyzed the publicly available bulk RNA\u2010seq on CD226\n                    <jats:sup>+<\/jats:sup>\n                    and CD226\n                    <jats:sup>\u2212<\/jats:sup>\n                    CD8\n                    <jats:sup>+<\/jats:sup>\n                    T\u00a0cells. Finally, we evaluated the impact of elevated cytokines\/chemokines on\n                    <jats:italic>CD226<\/jats:italic>\n                    expression. Our results showed that\n                    <jats:italic>CD226<\/jats:italic>\n                    \u2010expressing cells were significantly decreased within the effector memory and effector CD8\n                    <jats:sup>+<\/jats:sup>\n                    T\u00a0cell 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\n                    <jats:sup>+<\/jats:sup>\n                    CD226\n                    <jats:sup>\u2212<\/jats:sup>\n                    T\u00a0cells displayed an exhausted phenotype with reduced Runt\u2010related transcription factor 2 (\n                    <jats:italic>RUNX2<\/jats:italic>\n                    ) expression. Elevated levels of interleukin\u20106 (IL\u20106) and macrophage inflammatory protein\u20101 beta (MIP\u20101\u03b2) were inversely correlated with the frequency of CD8\n                    <jats:sup>+<\/jats:sup>\n                    CD226\n                    <jats:sup>+<\/jats:sup>\n                    T\u00a0cells and may contribute to the downregulation of CD226, possibly leading to T\u00a0cell dysfunction in CLL. Our findings highlight the critical role of CD8\n                    <jats:sup>+<\/jats:sup>\n                    CD226\n                    <jats:sup>+<\/jats:sup>\n                    RUNX2\n                    <jats:sup>hi<\/jats:sup>\n                    T\u00a0cells 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\u20106 and MIP\u20101\u03b2 to preserve polyfunctional CD8\n                    <jats:sup>+<\/jats:sup>\n                    CD226\n                    <jats:sup>+<\/jats:sup>\n                    T\u00a0cells as a promising immunotherapy strategy.\n                  <\/jats:p>","DOI":"10.1002\/1878-0261.13793","type":"journal-article","created":{"date-parts":[[2025,1,7]],"date-time":"2025-01-07T12:38:47Z","timestamp":1736253527000},"page":"1347-1370","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Polyfunctional\n                    <scp>CD<\/scp>\n                    8\n                    <sup>+<\/sup>\n                    <scp>CD<\/scp>\n                    226\n                    <sup>+<\/sup>\n                    <scp>RUNX<\/scp>\n                    2\n                    <sup>hi<\/sup>\n                    effector T\u00a0cells are diminished in advanced stages of chronic lymphocytic leukemia"],"prefix":"10.1002","volume":"19","author":[{"given":"Maryam","family":"Rezaeifar","sequence":"first","affiliation":[{"name":"Division of Foundational Sciences, Mike Petryk School of Dentistry University of Alberta  Edmonton Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shima","family":"Shahbaz","sequence":"additional","affiliation":[{"name":"Division of Foundational Sciences, Mike Petryk School of Dentistry University of Alberta  Edmonton Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anthea C.","family":"Peters","sequence":"additional","affiliation":[{"name":"Division of Medical Oncology, Department of Oncology University of Alberta  Edmonton Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Spencer B.","family":"Gibson","sequence":"additional","affiliation":[{"name":"Division of Medical Oncology, Department of Oncology University of Alberta  Edmonton Canada"},{"name":"Department of Biochemistry and Medical Genetics University of Alberta  Edmonton Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7215-2009","authenticated-orcid":false,"given":"Shokrollah","family":"Elahi","sequence":"additional","affiliation":[{"name":"Division of Foundational Sciences, Mike Petryk School of Dentistry University of Alberta  Edmonton Canada"},{"name":"Li Ka Shing Institute of Virology University of Alberta  Edmonton Canada"},{"name":"Women and Children Health Research Institute University of Alberta  Edmonton Canada"},{"name":"Cancer Research Institute of Northern Alberta, Faculty of Medicine and Dentistry University of Alberta  Edmonton 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