Polyfunctional CD8+CD226+RUNX2hi effector T cells are diminished in advanced stages of chronic lymphocytic leukemia

• Author / Creator

  Rezaeifar, Maryam

• Background: CD8+ T cells, in particular, those expressing the co-stimulatory molecule CD226, play crucial roles against malignancies. However, their role in chronic lymphocytic leukemia (CLL), which is an immunosuppressive disease, has yet to be explored. Therefore, further studies are needed to better understand the role of CD8+CD226+ T cells in CLL and other hematological cancers.
  We studied 64 CLL patients and 25 age-sex-matched healthy controls (HCs). We analyzed the proportion of CD226+ expressing cells among different CD8+ T cells subsets (e.g. naïve, central memory, effector memory, and effector) in CLL patients stratified by Rai stage and IGHV mutation status. Additionally, we compared the effector functions of CD8+CD226+ versus their CD226- counterparts. We also quantified the plasma concentrations of cytokines/chemokines in CLL and HCs. Furthermore, we reanalyzed publicly available RNAseq dataset on CD226+ and CD226- CD8+ T cells. Finally, we evaluated the effects of highly elevated cytokines/chemokines on the expression of CD226.
  We found that CD226+ expressing cells were significantly decreased within the effector memory and effector CD8+ T cells in CLL patients, particularly, those with advanced Rai stages and unmutated IGHV, a marker of poor prognosis. These cells displayed robust effector functions such as cytokine production, cytolytic activity, degranulation and proliferation capacity. Furthermore, the expression of chemokine receptors CLA, CCR4, and RUNX2 in CD8+CD226+ T cells suggested enhanced migration capability, particularly to the skin, potentially protecting against secondary skin tumors prevalent in CLL. Elevated levels of IL-6 and MIP-1β were inversely correlated with CD8+CD226+ T cell frequency and were implicated in the downregulation of CD226 expression, possibly contributing to T cell dysfunction in CLL. In contrast, CD8+CD226- T cells displayed an exhausted phenotype.
  Our findings highlight the critical role of CD8+CD226+RUNX2hi T cells in CLL and suggest that their reduction correlates with disease progression and poorer clinical outcomes. The inverse relationship between key inflammatory cytokines and CD226 expression offers potential therapeutic targets to restore CD8+ T cell functionality in CLL. This study underscores the importance of targeting CD8+CD226+ T cell modulation as a promising strategy in CLL immunotherapy.

• Subjects / Keywords

  • CD8 T cells
  • Chronic Lymphocytic Leukemia
  • CD226

• Graduation date

  Fall 2024

• Type of Item

  Thesis

• Degree

  Master of Science

• DOI

  https://doi.org/10.7939/r3-s0ej-gt63

• License

  This thesis is made available by the University of Alberta Library with permission of the copyright owner solely for non-commercial purposes. This thesis, or any portion thereof, may not otherwise be copied or reproduced without the written consent of the copyright owner, except to the extent permitted by Canadian copyright law.