KLF2 maintains lineage fidelity and suppresses CD8 T cell exhaustion during acute LCMV infection

Science, Journal Year: 2025, Volume and Issue: 387(6735)

Published: Jan. 2, 2025

Naïve CD8 T cells have the potential to differentiate into a spectrum of functional states during an immune response. How these developmental decisions are made and what mechanisms exist suppress differentiation toward alternative fates remains unclear. We employed in vivo CRISPR-Cas9–based perturbation sequencing assess role ~40 transcription factors (TFs) epigenetic modulators cell fate decisions. Unexpectedly, we found that knockout TF Klf2 resulted aberrant exhausted-like acute infection. KLF2 was required exhaustion-promoting TOX enable TBET drive effector differentiation. also necessary maintain polyfunctional tumor-specific progenitor state. Thus, provides lineage fidelity suppresses exhaustion program.

Language: Английский

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SMARCA4: Current status and future perspectives in non-small-cell lung cancer

Cancer Letters, Journal Year: 2022, Volume and Issue: 554, P. 216022 - 216022

Published: Nov. 28, 2022

SMARCA4, also known as transcription activator, is an ATP-dependent catalytic subunit of SWI/SNF (SWItch/Sucrose NonFermentable) chromatin-remodeling complexes that participates in the regulation chromatin structure and gene expression by supplying energy. As a tumor suppressor has aberrant ∼10% non-small-cell lung cancers (NSCLCs), SMARCA4 possesses many biological functions, including regulating expression, differentiation transcription. Furthermore, NSCLC patients with alterations have weak response to conventional chemotherapy poor prognosis. Therefore, mechanisms development urgently need be explored identify novel biomarkers precise therapeutic strategies for this subtype. This review systematically describes functions its role development, metastasis, functional epigenetics potential approaches NSCLCs alterations. Additionally, paper explores relationship regulatory shared mutually exclusive SMARCA2. We aim provide innovative treatment improve clinical outcomes

Language: Английский

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CRISPR screens for functional interrogation of immunity

Nature reviews. Immunology, Journal Year: 2022, Volume and Issue: 23(6), P. 363 - 380

Published: Dec. 8, 2022

Language: Английский

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The SWI/SNF chromatin remodeling complexes BAF and PBAF differentially regulate epigenetic transitions in exhausted CD8+ T cells

Immunity, Journal Year: 2023, Volume and Issue: 56(6), P. 1320 - 1340.e10

Published: June 1, 2023

Language: Английский

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Lipid metabolism reprogramming of CD8+ T cell and therapeutic implications in cancer

Cancer Letters, Journal Year: 2023, Volume and Issue: 567, P. 216267 - 216267

Published: June 12, 2023

Language: Английский

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Tissue-resident memory CAR T cells with stem-like characteristics display enhanced efficacy against solid and liquid tumors

Cell Reports Medicine, Journal Year: 2023, Volume and Issue: 4(6), P. 101053 - 101053

Published: May 23, 2023

Chimeric antigen receptor (CAR) T cells demonstrate remarkable success in treating hematological malignancies, but their effectiveness non-hematopoietic cancers remains limited. This study proposes enhancing CAR cell function and localization solid tumors by modifying the epigenome governing tissue-residency adaptation early memory differentiation. We identify that a key factor human tissue-resident (CAR-T

Language: Английский

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SUV39H1 Ablation Enhances Long-term CAR T Function in Solid Tumors

Cancer Discovery, Journal Year: 2023, Volume and Issue: 14(1), P. 120 - 141

Published: Oct. 31, 2023

Abstract Failure of adoptive T-cell therapies in patients with cancer is linked to limited expansion and persistence, even memory-prone 41BB-(BBz)–based chimeric antigen receptor (CAR) T cells. We show here that BBz-CAR stem/memory differentiation persistence can be enhanced through epigenetic manipulation the histone 3 lysine 9 trimethylation (H3K9me3) pathway. Inactivation H3K9 trimethyltransferase SUV39H1 enhances cell long-term protecting mice against tumor relapses rechallenges lung disseminated solid models up several months after CAR infusion. Single-cell transcriptomic (single-cell RNA sequencing) chromatin opening assay for transposase accessible chromatin) analyses tumor-infiltrating cells early reprogramming into self-renewing, stemlike populations decreased expression dysfunction genes all subpopulations. Therefore, methylation by optimizes functional cells, limiting relapses, providing protection rechallenges. Significance: Limited hinders therapeutic responses patients. targeting methyltransferase 41BB-based increasing stemness/memory differentiation. This opens a safe path enhancing tumors. See related article Jain et al., p. 142. featured Selected Articles from Issue, 5

Language: Английский

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Transcriptional and epigenetic regulators of human CD8+ T cell function identified through orthogonal CRISPR screens

Nature Genetics, Journal Year: 2023, Volume and Issue: 55(12), P. 2211 - 2223

Published: Nov. 9, 2023

Abstract Clinical response to adoptive T cell therapies is associated with the transcriptional and epigenetic state of product. Thus, discovery regulators gene networks their corresponding phenotypes has potential improve therapies. Here we developed pooled, CRISPR screening approaches systematically profile effects activating or repressing 120 on human CD8 + state. We found that BATF3 overexpression promoted specific features memory cells attenuated programs cytotoxicity, regulatory function, exhaustion. Upon chronic antigen stimulation, countered phenotypic signatures Moreover, enhanced potency CAR in both vitro vivo tumor models programmed a correlates positive clinical therapy. Finally, performed knockout screens defined cofactors downstream mediators network.

Language: Английский

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The effects of MYC on tumor immunity and immunotherapy

Cell Death Discovery, Journal Year: 2023, Volume and Issue: 9(1)

Published: March 25, 2023

Abstract The oncogene MYC is dysregulated in a host of human cancers, and as an important point convergence multitudinous oncogenic signaling pathways, it plays crucial role tumor immune regulation the microenvironment (TIME). Specifically, promotes expression immunosuppressive factors inhibits activation regulators. Undoubtedly, therapeutic strategy that targets can initiate new era cancer treatment. In this review, we summarize essential pathway immunity development status MYC-related therapies, including strategies targeting combined MYC-based immunotherapy. These studies have reported extraordinary insights into translational application treatment are conducive to emergence more effective immunotherapies for cancer.

Language: Английский

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Reprogramming T cell differentiation and exhaustion in CAR-T cell therapy

Journal of Hematology & Oncology, Journal Year: 2023, Volume and Issue: 16(1)

Published: Oct. 25, 2023

Abstract T cell differentiation is a highly regulated, multi-step process necessary for the progressive establishment of effector functions, immunological memory, and long-term control pathogens. In response to strong stimulation, as seen in severe or chronic infections cancer, cells acquire state hypo-responsiveness known exhaustion, limiting their function. Recent advances autologous chimeric antigen receptor (CAR)-T therapies have revolutionized treatment hematologic malignancies by taking advantage basic principles biology engineer products that promote long-lasting response. However, many patients’ remain unresponsive are prone recur. Discoveries biology, including identification key regulators offer novel opportunities durable impact on fate CAR-T after infusion. Such next-generation clinical implementation may result next leap forward cancer selected patients. this context, review summarizes foundational exhaustion describes how they can be utilized targeted further improve design efficacy therapies.

Language: Английский

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