Eomesodermin Increases Survival and IL-2 Responsiveness of Tumor-specific CD8+ T Cells in an Adoptive Transfer Model of Cancer Immunotherapy

Furusawa, Aki; Reiser, John; Sadashivaiah, Kavitha; Simpson, Haley; Banerjee, Arnob

doi:10.1097/cji.0000000000000206

Cited by 6 publications

(5 citation statements)

References 74 publications

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“…However, in the CLL mouse model, we observed no major impact of EOMES on the differentiation or functional capacity of CD8 + T cells, which might be due to the overlapping function of EOMES with the phylogenetically related transcription factor T-BET [ 5 , 8 ]. Our data, however, show that EOMES is required for efficient CD8 + T-cell expansion, which is in line with a previously described role of EOMES in enhancing CD8 + T-cell proliferation and survival and thereby, improving tumor control in a mouse model of cancer immunotherapy [ 42 ]. The importance of EOMES in adaptive immune control of tumors is further exemplified by a subset of CD4 + T cells that expresses EOMES and shows cytotoxic activity [ 43 ].…”

Section: Discussionsupporting

confidence: 91%

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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Section: Discussionsupporting

confidence: 91%

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

et al. 2021

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“…In addition, a recent report showed that constitutive expression of Eomes in tumor-specific CD8 T cells improved tumor rejection in a mouse lymphoma model system (EG7; ref. 32). These findings support a positive immune regulatory role of Eomes in cancer, which is in contrast to our observation that Eomes suppresses CD8 T-cell response in AML patients.…”

Section: Discussionsupporting

confidence: 70%

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

et al. 2019

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Acute myeloid leukemia (AML) is a devastating blood cancer with poor prognosis. Immunotherapy targeting inhibitory pathways to unleash the antileukemia T-cell response is a promising strategy for the treatment of leukemia, but we must first understand the underlying molecular mechanisms. Eomesodermin (Eomes) and T-bet are both T-box transcription factors that regulate CD8 þ T-cell responses in a context-specific manner. Here, we examined the role of these transcription factors in CD8 þ T-cell immunity in AML patients. We report that the frequency of Eomes þ T-bet low CD8 þ T cells increased in newly diagnosed AML. This cell subset produced fewer cytokines and displayed reduced killing capacity, whereas depletion of Eomes by siRNA reversed these functional defects. Furthermore, Eomes bound the promoter of T-cell immuno-globulin and ITIM domain (TIGIT) and positively regulated the expression of this inhibitory receptor on patient-derived T cells. A high frequency of Eomes þ T-bet low CD8 þ T cells was associated with poor response to induction chemotherapy and shorter overall survival in AML patients. These findings have significant clinical implications as they not only identify a predictive and prognostic biomarker for AML, but they also provide an important target for effective leukemia therapeutics.Significance: These findings reveal that a high frequency of Eomes þ T-bet low CD8 þ T cells predicts poor clinical outcome in AML and that targeting Eomes may provide a therapeutic benefit against AML.

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“…In this line, the coexpression of STAT4 and EOMES was indeed reported in effector T-cells. 64 Some molecules involved in T-cell cytotoxicity against tumor cells were upregulated (PRF1, GZM …).…”

Section: Discussionmentioning

confidence: 99%

PDL1 expression is associated with longer postoperative, survival in adrenocortical carcinoma

et al. 2019

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Adrenocortical carcinomas (ACCs) are heterogeneous cancers associated with a very poor prognosis. The improvement of prognostic tools and systemic therapy are urgently needed. Targeting the immune system using checkpoint inhibitors such as PD1/PDL1 inhibitors is an attractive novel therapeutic strategy for poor-prognosis tumors. Multiple clinical trials are ongoing, including in advanced ACC. However, PDL1 expression has been studied in ACC in only one heterogeneous series of 28 clinical samples. Here, we have retrospectively analyzed PDL1 mRNA expression in 146 clinical ACC samples and searched for correlations between expression and biological and clinicopathological data, including post-operative disease-free survival (DFS). PDL1 mRNA expression was heterogeneous across samples. "PDL1-high" tumors were not associated with the classical prognostic variables but were associated with longer DFS in both uni-and multivariate analyses. High PDL1 mRNA expression was associated with biological signs of the cytotoxic local immune response. Supervised analysis between "PDL1-high" and "PDL1-low" tumors identified a robust 370-gene signature whose ontology analysis suggested the existence in "PDL1-high" tumors of a cytotoxic T-cell response, however, associated with some degree of T-cell exhaustion. In conclusion, PDL1 mRNA expression refines the prognostication in ACC and high expression is associated with longer DFS. Clinical validation at the protein level and functional validation are required to fully understand the role of PDL1 in ACC. Reactivation of dormant tumor-infiltrating lymphocytes by PDL1-inhibitors could represent a promising strategy in "PDL1-high" ACCs, supporting the ongoing clinical trials.

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Eomesodermin Increases Survival and IL-2 Responsiveness of Tumor-specific CD8+ T Cells in an Adoptive Transfer Model of Cancer Immunotherapy

Cited by 6 publications

References 74 publications

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

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

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

PDL1 expression is associated with longer postoperative, survival in adrenocortical carcinoma

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