Eomes+T-betlow CD8+ T Cells Are Functionally Impaired and Are Associated with Poor Clinical Outcome in Patients with Acute Myeloid Leukemia

Jia, Bei; Zhao, Chenchen; Rakszawski, Kevin; Claxton, David F.; Ehmann, W. Christopher; Rybka, Witold B.; Mineishi, Shin; Wang, Ming; Shike, Hiroko; Bayerl, Michael G.; Sivik, Jeffrey; Schell, Todd D.; Hohl, Raymond J.; Zheng, Hong

doi:10.1158/0008-5472.can-18-3107

Cited by 52 publications

(35 citation statements)

References 51 publications

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“…The experiment protocol was described in our previous published studies [47]. Briefly, purified CD8 T cells derived from PBMCs of AML patients were co-cultured with T2 cells that were pulsed with 10 μM WT1 126–134 peptide, in the presence of 50 IU IL-2 (R&D system) for 6 days.…”

Section: Methodsmentioning

confidence: 99%

Downregulation of CD73 associates with T cell exhaustion in AML patients

et al. 2019

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Background Successful treatment for acute myeloid leukemia (AML) remains challenging. Inhibiting immune checkpoint to enhance anti-tumor response is an attractive strategy for effective leukemia therapeutics. CD73 is a recently recognized immune checkpoint mediator that is highly expressed on tumor cells and stromal cells in tumor microenvironment. The ectonucleotidase activity of CD73 catalyzes AMP to adenosine, which subsequently inhibits anti-tumor immune responses. In this study, we aim to explore the effect of CD73 in AML. Methods Peripheral blood samples collected from patients with newly diagnosed AML ( n = 27) were used in this study. CD73 expression on each immune cell component was examined by flow cytometry. Phenotypic study of CD73-expressing T cells and analysis of the correlation between CD73 and other immune checkpoints were performed using flow cytometry-based assays. Functional status of CD73 + vs. CD73 − T cells was assessed in an in vitro cytokine release assay upon CD3/CD28 antibody stimulation. Results In contrast to the long recognized immune suppressive effect of CD73-adenosine signaling in tumor tissue, we made a striking observation that in AML, CD73 expression on CD8 T cells associates with an increased immune response. CD73 + CD8 T cells are more functional, whereas CD73 − CD8 T cells exhibit features of exhaustion manifested by high expression of inhibitory receptors such as PD-1 and TIGIT, increased intracellular expression of Eomes, reduced capacity of cytokine production, and high susceptibility to apoptosis. Conclusions Our data highlight the potential of CD73 as a double-edged sword in anti-leukemia immunity and argue strongly for the combinational treatment by adding immune checkpoint inhibitors to the CD73-targeting approaches.

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Section: Methodsmentioning

confidence: 99%

Downregulation of CD73 associates with T cell exhaustion in AML patients

et al. 2019

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“…As a master regulator of CD8 + effector and memory T cells, EOMES is critical for T-cell-mediated immune responses against pathogens [4,[6][7][8]. An accumulation of EOMES-expressing CD8 + T cells that show characteristics of exhausted cells was observed in several tumor entities [9][10][11][12]. 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].…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2021

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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.

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“…1 A,B). Recent studies have shown that low expression levels of T-bet and high expression levels of Eomes are associated with functionally impaired CD8 + T cells 14 , 15 . In line with these findings, EV10-specific CD8 + T cells primed in the presence of TLR9L exhibited lower T-bet/Eomes ratios compared with EV10-specific CD8 + T cells primed in the presence of TLR8L or 2′3′-cGAMP (Fig.…”

Section: Resultsmentioning

confidence: 99%

The TLR9 ligand CpG ODN 2006 is a poor adjuvant for the induction of de novo CD8+ T-cell responses in vitro

Papagno

Kuse

Lissina

et al. 2020

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Toll-like receptor 9 (TLR9) agonists have gained traction in recent years as potential adjuvants for the induction of adaptive immune responses. It has nonetheless remained unclear to what extent such ligands can facilitate the priming events that generate antigen-specific effector and/or memory CD8 + T-cell populations. We used an established in vitro model to prime naive precursors from human peripheral blood mononuclear cells in the presence of various adjuvants, including CpG ODN 2006, a synthetic oligonucleotide TLR9 ligand (TLR9L). Unexpectedly, we found that TLR9L induced a suboptimal inflammatory milieu and promoted the antigen-driven expansion and functional maturation of naive CD8 + T cells ineffectively compared with either ssRNA40 or 2′3′-cGAMP, which activate other pattern recognition receptors (PRRs). TLR9L also inhibited the priming efficacy of 2′3′-cGAMP. Collectively, these results suggest that TLR9L is unlikely to be a good candidate for the optimal induction of de novo CD8 + T-cell responses, in contrast to adjuvants that operate via discrete PRRs.

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Eomes+T-betlow CD8+ T Cells Are Functionally Impaired and Are Associated with Poor Clinical Outcome in Patients with Acute Myeloid Leukemia

Cited by 52 publications

References 51 publications

Downregulation of CD73 associates with T cell exhaustion in AML patients

Downregulation of CD73 associates with T cell exhaustion in AML patients

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

The TLR9 ligand CpG ODN 2006 is a poor adjuvant for the induction of de novo CD8+ T-cell responses in vitro

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