Epigenetic strategies to boost CAR T cell therapy

Akbari, Behnia; Ghahri-Saremi, Navid; Soltantoyeh, Tahereh; Hadjati, Jamshid; Ghassemi, Saba

doi:10.1016/j.ymthe.2021.08.003

Cited by 34 publications

(27 citation statements)

References 221 publications

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“…It is known that DNA methyltransferase (DNMT) mediates DNA methylation, which implies that DNMT participated in the process of T cell differentiation ( Pace and Amigorena, 2020 ; Akbari et al, 2021 ). Ladle et al (2016) have shown that the knocking out DNMT3a gene (DNMT3a – ) skews early effector CD8 + T cells to differentiate into memory precursor phenotype (CD127 + KLRG1 – ) rather than terminal effector phenotype (CD127 – KLRG1 + ).…”

Section: Enzymatic Factors Regulating T Cell Function Through Epigenetic Remodelingmentioning

confidence: 99%

“…Altering enzymatic factors can skew CD8 + T cell effector function. Thus, identifying the mechanism of methylation-associated enzymes remodeling chromatin and DNA methylation in CD8 + T cells provides novel insights into therapeutic design T cell-based therapy ( Pace and Amigorena, 2020 ; Akbari et al, 2021 ; Frias et al, 2021 ).…”

Section: Enzymatic Factors Regulating T Cell Function Through Epigenetic Remodelingmentioning

confidence: 99%

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The Interplay Between Epigenetic Regulation and CD8+ T Cell Differentiation/Exhaustion for T Cell Immunotherapy

Wong

Yin

Lam

et al. 2022

Front. Cell Dev. Biol.

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Effective immunotherapy treats cancers by eradicating tumourigenic cells by activated tumour antigen-specific and bystander CD8+ T-cells. However, T-cells can gradually lose cytotoxicity in the tumour microenvironment, known as exhaustion. Recently, DNA methylation, histone modification, and chromatin architecture have provided novel insights into epigenetic regulations of T-cell differentiation/exhaustion, thereby controlling the translational potential of the T-cells. Thus, developing strategies to govern epigenetic switches of T-cells dynamically is critical to maintaining the effector function of antigen-specific T-cells. In this mini-review, we 1) describe the correlation between epigenetic states and T cell phenotypes; 2) discuss the enzymatic factors and intracellular/extracellular microRNA imprinting T-cell epigenomes that drive T-cell exhaustion; 3) highlight recent advances in epigenetic interventions to rescue CD8+ T-cell functions from exhaustion. Finally, we express our perspective that regulating the interplay between epigenetic changes and transcriptional programs provides translational implications of current immunotherapy for cancer treatments.

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Section: Enzymatic Factors Regulating T Cell Function Through Epigenetic Remodelingmentioning

confidence: 99%

Section: Enzymatic Factors Regulating T Cell Function Through Epigenetic Remodelingmentioning

confidence: 99%

The Interplay Between Epigenetic Regulation and CD8+ T Cell Differentiation/Exhaustion for T Cell Immunotherapy

Wong

Yin

Lam

et al. 2022

Front. Cell Dev. Biol.

View full text Add to dashboard Cite

show abstract

“…via ICB or BiTE) or administered as cytotoxic T-cell products (e.g. CAR T cells) (Akbari et al, 2021).…”

Section: Rationale For Novel Immunotherapy-based Combinations In B-cell Lymphomasmentioning

confidence: 99%

Epigenetic, Metabolic, and Immune Crosstalk in Germinal-Center-Derived B-Cell Lymphomas: Unveiling New Vulnerabilities for Rational Combination Therapies

Serganova

Chakraborty

Yamshon

et al. 2022

Front. Cell Dev. Biol.

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B-cell non-Hodgkin lymphomas (B-NHLs) are highly heterogenous by genetic, phenotypic, and clinical appearance. Next-generation sequencing technologies and multi-dimensional data analyses have further refined the way these diseases can be more precisely classified by specific genomic, epigenomic, and transcriptomic characteristics. The molecular and genetic heterogeneity of B-NHLs may contribute to the poor outcome of some of these diseases, suggesting that more personalized precision-medicine approaches are needed for improved therapeutic efficacy. The germinal center (GC) B-cell like diffuse large B-cell lymphomas (GCB-DLBCLs) and follicular lymphomas (FLs) share specific epigenetic programs. These diseases often remain difficult to treat and surprisingly do not respond advanced immunotherapies, despite arising in secondary lymphoid organs at sites of antigen recognition. Epigenetic dysregulation is a hallmark of GCB-DLBCLs and FLs, with gain-of-function (GOF) mutations in the histone methyltransferase EZH2, loss-of-function (LOF) mutations in histone acetyl transferases CREBBP and EP300, and the histone methyltransferase KMT2D representing the most prevalent genetic lesions driving these diseases. These mutations have the common effect to disrupt the interactions between lymphoma cells and the immune microenvironment, via decreased antigen presentation and responsiveness to IFN-γ and CD40 signaling pathways. This indicates that immune evasion is a key step in GC B-cell lymphomagenesis. EZH2 inhibitors are now approved for the treatment of FL and selective HDAC3 inhibitors counteracting the effects of CREBBP LOF mutations are under development. These treatments can help restore the immune control of GCB lymphomas, and may represent optimal candidate agents for more effective combination with immunotherapies. Here, we review recent progress in understanding the impact of mutant chromatin modifiers on immune evasion in GCB lymphomas. We provide new insights on how the epigenetic program of these diseases may be regulated at the level of metabolism, discussing the role of metabolic intermediates as cofactors of epigenetic enzymes. In addition, lymphoma metabolic adaptation can negatively influence the immune microenvironment, further contributing to the development of immune cold tumors, poorly infiltrated by effector immune cells. Based on these findings, we discuss relevant candidate epigenetic/metabolic/immune targets for rational combination therapies to investigate as more effective precision-medicine approaches for GCB lymphomas.

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“…It has become clear that epigenetic modulation can enhance CAR-T cell persistence and function as well as trafficking within an immunosuppressive TME [203,204]. In an attempt to decipher the mechanisms underlying a delayed exceptional response to CD19 CAR-T therapy, Fraietta et al [205] suggested that TET2-disrupted CAR-T cells can acquire a central memory phenotype through altered T cell differentiation as a result of epigenetic modulation.…”

Section: Advances Of Epi-cell Therapy For Solid and Hematological Can...mentioning

confidence: 99%

Epi‐immunotherapy for cancers: rationales of epi‐drugs in combination with immunotherapy and advances in clinical trials

Liu

et al. 2022

Cancer Communications

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Over the last two decades, several epi‐drugs, immune checkpoint inhibitors (ICIs) and adoptive cell therapies have received clinical approval for use in certain types of cancer. However, monotherapy with epi‐drugs or ICIs has shown limited efficacy in most cancer patients. Epigenetic agents have been shown to regulate the crosstalk between the tumor and host immunity to alleviate immune evasion, suggesting that epi‐drugs can potentially synergize with immunotherapy. In this review, we discuss recent insights into the rationales of incorporating epigenetic therapy into immunotherapy, called epi‐immunotherapy, and focus on an update of current clinical trials in both hematological and solid malignancies. Furthermore, we outline the future challenges and strategies in the field of cancer epi‐immunotherapy.

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Epigenetic strategies to boost CAR T cell therapy

Cited by 34 publications

References 221 publications

The Interplay Between Epigenetic Regulation and CD8+ T Cell Differentiation/Exhaustion for T Cell Immunotherapy

The Interplay Between Epigenetic Regulation and CD8+ T Cell Differentiation/Exhaustion for T Cell Immunotherapy

Epigenetic, Metabolic, and Immune Crosstalk in Germinal-Center-Derived B-Cell Lymphomas: Unveiling New Vulnerabilities for Rational Combination Therapies

Epi‐immunotherapy for cancers: rationales of epi‐drugs in combination with immunotherapy and advances in clinical trials

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