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EOMES is essential for antitumor activity of CD8⁺ T cells in chronic lymphocytic leukemia.

ABSTRACT: Genome-wide association studies identified a single-nucleotide polymorphism (SNP) affecting the transcription factor Eomesodermin (EOMES) associated with a significantly increased risk to develop chronic lymphocytic leukemia (CLL). Epigenetic analyses, RNA sequencing, and flow cytometry revealed that EOMES is not expressed in CLL cells, but in CD8⁺ T cells for which EOMES is a known master regulator. We thus hypothesized that the increased CLL risk associated with the EOMES SNP might be explained by its negative impact on CD8⁺ T-cell-mediated immune control of CLL. Flow cytometry analyses revealed a higher EOMES expression in CD8⁺ T cells of CLL patients compared to healthy individuals, and an accumulation of PD-1⁺ EOMES⁺ CD8⁺ T cells in lymph nodes rather than blood or bone marrow in CLL. This was in line with an observed expansion of EOMES⁺ CD8⁺ T cells in the spleen of leukemic Eµ-TCL1 mice. As EOMES expression was highest in CD8⁺ T cells that express inhibitory receptors, an involvement of EOMES in T-cell exhaustion and dysfunction seems likely. Interestingly, Eomes-deficiency in CD8⁺ T cells resulted in their impaired expansion associated with decreased CLL control in mice. Overall, these observations suggest that EOMES is essential for CD8⁺ T-cell expansion and/or maintenance, and therefore involved in adaptive immune control of CLL.

SUBMITTER: Llao-Cid L

PROVIDER: S-EPMC8550953 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundCD8+ T cells play an essential role against tumors but the role of human CD8+CD26+ T cell subset against tumors, in particular, haematological cancers such as chronic lymphocytic leukemia (CLL) remains unknown. Although CD4+CD26high T cells are considered for adoptive cancer immunotherapy, the role of CD8+CD26+ T cells is ill-defined. Therefore, further studies are required to better determine the role of CD8+CD26+ T cells in solid tumors and haematological cancers.MethodsWe studied 55 CLL and 44 age-sex-matched healthy controls (HCs). The expression of CD26 on different T cell subsets (e.g. naïve, memory, effector, and etc.) was analyzed. Also, functional properties of CD8+CD26+ and CD8+CD26- T cells were evaluated. Finally, the plasma cytokine/chemokine and Galectin-9 (Gal-9) levels were examined.ResultsCD26 expression identifies three CD8+ T cell subsets with distinct immunological properties. While CD26negCD8+ T cells are mainly transitional, effector memory and effectors, CD26lowCD8+ T cells are mainly naïve, stem cell, and central memory but CD26high T cells are differentiated to transitional and effector memory. CD26+CD8+ T cells are significantly reduced in CLL patients versus HCs. CD26high cells are enriched with Mucosal Associated Invariant T (MAIT) cells co-expressing CD161TVα7.2 and IL-18Rα. Also, CD26high cells have a rich chemokine receptor profile (e.g. CCR5 and CCR6), profound cytokine (TNF-α, IFN-γ, and IL-2), and cytolytic molecules (Granzyme B, K, and perforin) expression upon stimulation. CD26high and CD26low T cells exhibit significantly lower frequencies of CD160, 2B4, TIGIT, ICOS, CD39, and PD-1 but higher levels of CD27, CD28, and CD73 versus CD26neg cells. To understand the mechanism linked to CD26high depletion, we found that malignant B cells by shedding Galectin-9 (Gal-9) contribute to the elevation of plasma Gal-9 in CLL patients. In turn, Gal-9 and the inflammatory milieu (IL-18, IL-12, and IL-15) in CLL patients contribute to increased apoptosis of CD26high T cells.ConclusionsOur results demonstrate that CD26+ T cells possess a natural polyfunctionality to traffic and exhibit effector functions and resist exhaustion. Therefore, they can be proposed for adoptive cancer immunotherapy. Finally, neutralizing and/or inhibiting Gal-9 may preserve CD26highCD8+ T cells in CLL.

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EOMES is essential for antitumor activity of CD8⁺ T cells in chronic lymphocytic leukemia.

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OmicsDI is part of the ELIXIR infrastructure

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Dataset Information

EOMES is essential for antitumor activity of CD8+ T cells in chronic lymphocytic leukemia.

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OmicsDI is part of the ELIXIR infrastructure

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EOMES is essential for antitumor activity of CD8⁺ T cells in chronic lymphocytic leukemia.