EOMES is essential for antitumor activity of CD8+ T cells in chronic lymphocytic leukemia
Laura Llaó Cid, Philipp M. Roessner, Vicente Chapaprieta, Selcen Öztürk, Tobias Roider, Marie Bordas, Ana Ízcue, Dolors Colomer, Sascha Dietrich, Stephan Stilgenbauer, Bola S. Hanna, José I. Martín‐Subero, Martina Seiffert
Abstract
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.