Exhausted T cells and epigenetic status

Zeng, Ziqing; Feng, Wei; Ren, Xiubao

doi:10.20892/j.issn.2095-3941.2020.0338

Cited by 39 publications

(25 citation statements)

References 97 publications

(165 reference statements)

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“…Complementing these approaches, total CD8 + T ex were shown to possess a fixed chromatin state distinct from effector and memory cells by~6,000 open chroman regions before or after exposure to anti-PD-L1 (21,63,64). This reinforces that terminal CD8 + T ex represents a distinct lineage unable to differentiate into bona fide memory cells.…”

Section: Transcriptional and Epigenetic Events Critical For The Establishment Of Terminal Exhaustionmentioning

confidence: 80%

“…Downstream from TCF-1-mediated subsistence of PD-1 lo CD8 + T ex , thymocyte selection-associated high-mobility group (HMG) box protein, TOX, becomes co-upregulated alongside PD-1 and is associated with the epigenetic signatures demarcating terminal lineage commitment within PD-1 hi CD8 + T ex (24,56,(65)(66)(67). TOX is a nuclear protein that binds DNA in a structure-dependent manner (not sequence-dependent) (64). TOX directly interacts with histone acetyltransferase binding to ORC1 (HBO1) and indirectly coordinates activity with DNA methyltransferases 3A (DNMT3A), 3B (DNMT3B), and enhancer of zeste homolog 2 (EZH2) to epigenetically fix CD8 + T ex towards terminal exhaustion (64).…”

Section: Transcriptional and Epigenetic Events Critical For The Establishment Of Terminal Exhaustionmentioning

confidence: 99%

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CD8+ T Cell Exhaustion in Cancer

et al. 2021

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A paradigm shift in the understanding of the exhausted CD8+ T cell (Tex) lineage is underway. Originally thought to be a uniform population that progressively loses effector function in response to persistent antigen, single-cell analysis has now revealed that CD8+ Tex is composed of multiple interconnected subpopulations. The heterogeneity within the CD8+ Tex lineage is comprised of immune checkpoint blockade (ICB) permissive and refractory subsets termed stem-like and terminally differentiated cells, respectively. These populations occupy distinct peripheral and intratumoral niches and are characterized by transcriptional processes that govern transitions between cell states. This review presents key findings in the field to construct an updated view of the spatial, transcriptional, and functional heterogeneity of anti-tumoral CD8+ Tex. These emerging insights broadly call for (re-)focusing cancer immunotherapies to center on the driver mechanism(s) underlying the CD8+ Tex developmental continuum aimed at stabilizing functional subsets.

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Section: Transcriptional and Epigenetic Events Critical For The Establishment Of Terminal Exhaustionmentioning

confidence: 80%

Section: Transcriptional and Epigenetic Events Critical For The Establishment Of Terminal Exhaustionmentioning

confidence: 99%

CD8+ T Cell Exhaustion in Cancer

et al. 2021

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“…There is strong evidence showing that LAG-3 protein expression is related to an “epigenetic exhaustion state” in T cells [ 75 ]. From these studies, it can be concluded that DNA and histone modifications are certainly involved in LAG-3 upregulation in cancer, suggesting that epigenetic modifications could be useful as a potential predictive biomarker of response to immune checkpoint blockade immunotherapies.…”

Section: Regulation Of Lag-3 Expressionmentioning

confidence: 99%

Understanding LAG-3 Signaling

Chocarro

Blanco

Zuazo

et al. 2021

IJMS

118

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Lymphocyte activation gene 3 (LAG-3) is a cell surface inhibitory receptor with multiple biological activities over T cell activation and effector functions. LAG-3 plays a regulatory role in immunity and emerged some time ago as an inhibitory immune checkpoint molecule comparable to PD-1 and CTLA-4 and a potential target for enhancing anti-cancer immune responses. LAG-3 is the third inhibitory receptor to be exploited in human anti-cancer immunotherapies, and it is considered a potential next-generation cancer immunotherapy target in human therapy, right next to PD-1 and CTLA-4. Unlike PD-1 and CTLA-4, the exact mechanisms of action of LAG-3 and its relationship with other immune checkpoint molecules remain poorly understood. This is partly caused by the presence of non-conventional signaling motifs in its intracellular domain that are different from other conventional immunoregulatory signaling motifs but with similar inhibitory activities. Here we summarize the current understanding of LAG-3 signaling and its role in LAG-3 functions, from its mechanisms of action to clinical applications.

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“…Dysfunctional and/or immunosuppressive T cells in AML have been previously described, specifically in peripheral blood (14)(15)(16)(17)(18). AML LSCs express different co-stimulatory and coinhibitory ligands, and the efficacy of ICIs is identifiably lower in leukemia than in solid tumors (11).…”

Section: Discussionmentioning

confidence: 99%

“…Comparably, some IC receptors, including PD-1, were upregulated in CD4 + or CD8 + T cells of AML patients versus healthy controls in the present study. Different studies have demonstrated that aberrant epigenetic alterations, such as histone remodeling and DNA methylation play a crucial role in the dysregulation of ICs during carcinogenesis (14,15,31). In addition, DNA hypomethylating agents (HMAs) such as azacitidine and decitabine upregulate the expression of PD-L1 in solid tumors (16) and AML (17) and thereby dampen the anti-tumor immune response.…”

Section: Discussionmentioning

confidence: 99%

Epigenetic Silencing of Immune-Checkpoint Receptors in Bone Marrow- Infiltrating T Cells in Acute Myeloid Leukemia

et al. 2021

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BackgroundImmune-checkpoint (IC) inhibitors have revolutionized the treatment of multiple solid tumors and defined lymphomas, but they are largely ineffective in acute myeloid leukemia (AML). The reason why especially PD1/PD-L1 blocking agents are not efficacious is not well-understood but it may be due to the contribution of different IC ligand/receptor interactions that determine the function of T cells in AML.MethodsTo analyze the interactions of IC ligands and receptors in AML, we performed a comprehensive transcriptomic analysis of FACS-purified leukemia stem/progenitor cells and paired bone marrow (BM)-infiltrating CD4+ and CD8+ T cells from 30 patients with AML. The gene expression profiles of activating and inhibiting IC ligands and receptors were correlated with the clinical data. Epigenetic mechanisms were studied by inhibiting the histone deacetylase with valproic acid or by gene silencing of PAC1.ResultsWe observed that IC ligands and receptors were mainly upregulated in leukemia stem cells. The gene expression of activating IC ligands and receptors correlated with improved prognosis and vice versa. In contrast, the majority of IC receptor genes were downregulated in BM-infiltrating CD8+ T cells and partially in CD4+ T cells, due to pathological chromatin remodeling via histone deacetylation. Therefore, treatment with histone deacetylase inhibitor (HDACi) or silencing of PAC1, as a T cell-specific epigenetic modulator, significantly increased the expression of IC receptors and defined effector molecules in CD8+ T cells.ConclusionsOur results suggest that CD8+ T cells in AML are dysfunctional mainly due to pathological epigenetic silencing of activating IC receptors rather than due to signaling by immune inhibitory IC receptors, which may explain the limited efficacy of antibodies that block immune-inhibitory ICs in AML.

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Exhausted T cells and epigenetic status

Cited by 39 publications

References 97 publications

CD8+ T Cell Exhaustion in Cancer

CD8+ T Cell Exhaustion in Cancer

Understanding LAG-3 Signaling

Epigenetic Silencing of Immune-Checkpoint Receptors in Bone Marrow- Infiltrating T Cells in Acute Myeloid Leukemia

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