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

Laura Llaó-Cid,Stephan Stilgenbauer,Martina Seiffert,José Ignacio Martín-Subero,Bola Hanna,Sascha Dietrich,Marie Bordas,Philipp M Roessner,Tobias Roider,Selcen Öztürk,Vicente Chapaprieta,Dolors Colomer,Ana Izcue

doi:10.1038/s41375-021-01198-1

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.

Highlights

IntroductionEpigenetic analyses have revealed, that the single-nucleotide polymorphism (SNP) associated with EOMES is located in a heterochromatic region in chronic lymphocytic leukemia (CLL) cells and normal B cells, independently of the presence or absence of the risk variant [2]
T-cell exhaustion was first described in chronic viral infections as a dysfunctional state of CD8+ T cells that develops due to persistent antigen exposure and is characterized by the coexpression of multiple inhibitory receptors, including programmed cell death 1 (PD-1), lymphocyte activating gene 3 (LAG3), T-cell immunoreceptor with Ig and ITIM domains (TIGIT), and cluster of differentiation 244 (CD244), defective effector function, and an altered transcriptional and epigenetic state [9, 13,14,15,16]
We investigated the expression of EOMES transcription factor in tumor and T cells from peripheral blood (PB) and lymph nodes (LNs) of chronic lymphocytic leukemia (CLL) patients and its relation to T-cell exhaustion

Summary

Introduction

Epigenetic analyses have revealed, that the SNP associated with EOMES is located in a heterochromatic region in CLL cells and normal B cells, independently of the presence or absence of the risk variant [2]. T-cell exhaustion was first described in chronic viral infections as a dysfunctional state of CD8+ T cells that develops due to persistent antigen exposure and is characterized by the coexpression of multiple inhibitory receptors, including programmed cell death 1 (PD-1), lymphocyte activating gene 3 (LAG3), T-cell immunoreceptor with Ig and ITIM domains (TIGIT), and cluster of differentiation 244 (CD244), defective effector function, and an altered transcriptional and epigenetic state [9, 13,14,15,16]. A role for EOMES in T-cell dysfunction following continuous activation of CD8+ T cells was suggested [15, 17]

Methods

Results

Conclusion