Molecular Mechanisms Governing CD8 T Cell Differentiation and Checkpoint Inhibitor Response in Cancer DOI
L Rausch, Axel Kallies

Annual Review of Immunology, Год журнала: 2025, Номер 43(1), С. 515 - 543

Опубликована: Апрель 25, 2025

CD8 T cells play a critical role in antitumor immunity. However, over time, they often become dysfunctional or exhausted and ultimately fail to control tumor growth. To effectively harness for cancer immunotherapy, detailed understanding of the mechanisms that govern their differentiation function is crucial. This review summarizes our current knowledge molecular pathways regulate cell heterogeneity chronic infection outlines how respond therapeutic checkpoint blockade. We explore cell–intrinsic –extrinsic factors influence differentiation, fate choices, functional states dictate response therapy. Identifying orchestrate long-term immunity development persistence are steps toward improving immunotherapy.

Язык: Английский

Principles and therapeutic applications of adaptive immunity DOI Creative Commons
Hongbo Chi, Marion Pepper, Paul G. Thomas

и другие.

Cell, Год журнала: 2024, Номер 187(9), С. 2052 - 2078

Опубликована: Апрель 1, 2024

Adaptive immunity provides protection against infectious and malignant diseases. These effects are mediated by lymphocytes that sense respond with targeted precision to perturbations induced pathogens tissue damage. Here, we review key principles underlying adaptive orchestrated distinct T cell B populations their extensions disease therapies. We discuss the intracellular intercellular processes shaping antigen specificity recognition in immune activation lymphocyte functions mediating effector memory responses. also describe how balance protective autoimmunity immunopathology, including during tolerance, response chronic stimulation, adaptation non-lymphoid tissues coordinating homeostasis. Finally, extracellular signals cell-intrinsic programs underpinning conclude summarizing advances vaccination engineering responses for therapeutic interventions. A deeper understanding of these holds promise uncovering new means improve human health.

Язык: Английский

Процитировано

74
CRISPR–Cas9 applications in T cells and adoptive T cell therapies DOI Creative Commons
Xiaoying Chen,

Shuhan Zhong,

Yonghao Zhan

и другие.

Cellular & Molecular Biology Letters, Год журнала: 2024, Номер 29(1)

Опубликована: Апрель 12, 2024

Abstract T cell immunity is central to contemporary cancer and autoimmune therapies, encompassing immune checkpoint blockade adoptive therapies. Their diverse characteristics can be reprogrammed by different challenges dependent on antigen stimulation levels, metabolic conditions, the degree of inflammation. cell-based therapeutic strategies are gaining widespread adoption in oncology treating inflammatory conditions. Emerging researches reveal that clustered regularly interspaced palindromic repeats–associated protein 9 (CRISPR–Cas9) genome editing has enabled cells more adaptable specific microenvironments, opening door advanced therapies preclinical clinical trials. CRISPR–Cas9 edit both primary engineered cells, including CAR-T TCR-T, vivo vitro regulate differentiation activation states. This review first provides a comprehensive summary role its applications studies for We also explore application CRISPR screen high-throughput technology anticipate current limitations CRISPR–Cas9, off-target effects delivery challenges, envisioned improvements related technologies disease screening, diagnosis, treatment.

Язык: Английский

Процитировано

19
KLF2 maintains lineage fidelity and suppresses CD8 T cell exhaustion during acute LCMV infection DOI
Eric Fagerberg, John Attanasio, Christine Dien

и другие.

Science, Год журнала: 2025, Номер 387(6735)

Опубликована: Янв. 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.

Язык: Английский

Процитировано

8
Exploring the impact of environmental factors on male reproductive health through epigenetics DOI
Yi Zhang, Jingyan Song, Zhen‐Gao Sun

и другие.

Reproductive Toxicology, Год журнала: 2025, Номер 132, С. 108832 - 108832

Опубликована: Янв. 6, 2025

Язык: Английский

Процитировано

6
Chromatin remodellers as therapeutic targets DOI
Hayden A. Malone, Charles W.M. Roberts

Nature Reviews Drug Discovery, Год журнала: 2024, Номер 23(9), С. 661 - 681

Опубликована: Июль 16, 2024

Язык: Английский

Процитировано

15
Distinct epigenomic landscapes underlie tissue-specific memory T cell differentiation DOI

Frank A. Buquicchio,

Raíssa Fonseca, Patrick Yan

и другие.

Immunity, Год журнала: 2024, Номер 57(9), С. 2202 - 2215.e6

Опубликована: Июль 22, 2024

Язык: Английский

Процитировано

14
Targeting SWI/SNF Complexes in Cancer: Pharmacological Approaches and Implications DOI Creative Commons

Megan R. Dreier,

Jasmine Walia,

Ivana L. de la Serna

и другие.

Epigenomes, Год журнала: 2024, Номер 8(1), С. 7 - 7

Опубликована: Фев. 4, 2024

SWI/SNF enzymes are heterogeneous multi-subunit complexes that utilize the energy from ATP hydrolysis to remodel chromatin structure, facilitating transcription, DNA replication, and repair. In mammalian cells, distinct sub-complexes, including cBAF, ncBAF, PBAF exhibit varying subunit compositions have different genomic functions. Alterations in complex sub-complex functions a prominent feature cancer, making them attractive targets for therapeutic intervention. Current strategies cancer therapeutics involve use of pharmacological agents designed bind disrupt activity or specific sub-complexes. Inhibitors targeting catalytic subunits, SMARCA4/2, small molecules binding bromodomains primary approaches suppressing function. Proteolysis-targeting chimeras (PROTACs) were generated by covalent linkage bromodomain ATPase-binding ligand an E3 ligase-binding moiety. This engineered connection promotes degradation enhancing extending impact this intervention some cases. Extensive preclinical studies underscored potential these drugs across diverse types. Encouragingly, progressed research clinical trials, indicating promising stride toward development effective

Язык: Английский

Процитировано

13
Collaboration between distinct SWI/SNF chromatin remodeling complexes directs enhancer selection and activation of macrophage inflammatory genes DOI
Jingwen Liao, Josephine Ho, Mannix J. Burns

и другие.

Immunity, Год журнала: 2024, Номер 57(8), С. 1780 - 1795.e6

Опубликована: Июнь 5, 2024

Язык: Английский

Процитировано

11
Chromatin Remodelers Are Regulators of the Tumor Immune Microenvironment DOI
Apoorvi Chaudhri, Gregory Lizée, Patrick Hwu

и другие.

Cancer Research, Год журнала: 2024, Номер 84(7), С. 965 - 976

Опубликована: Янв. 24, 2024

Abstract Immune checkpoint inhibitors show remarkable responses in a wide range of cancers, yet patients develop adaptive resistance. This necessitates the identification alternate therapies that synergize with immunotherapies. Epigenetic modifiers are potent mediators tumor-intrinsic mechanisms and have been shown to regulate immune response genes, making them prime targets for therapeutic combinations inhibitors. Some success has observed early clinical studies combined immunotherapy agents targeting DNA methylation histone modification; however, less is known about chromatin remodeler-targeted therapies. Here, we provide discussion on regulation tumor immunogenicity by remodeling SWI/SNF complex through multiple associated broadly include IFN signaling, damage, mismatch repair, oncogenic programs, polycomb-repressive antagonism. Context-dependent subunits can elicit opportunities synthetic lethality reduce T-cell exhaustion. In summary, alongside significance predicting outcomes, their ability modulate landscape offers intervention.

Язык: Английский

Процитировано

10
Brd7 loss reawakens dormant metastasis initiating cells in lung by forging an immunosuppressive niche DOI Creative Commons
Jayanta Mondal, Junfeng Zhang,

Qing Feng

и другие.

Nature Communications, Год журнала: 2025, Номер 16(1)

Опубликована: Фев. 5, 2025

Metastasis in cancer is influenced by epigenetic factors. Using an vivo screen, we demonstrate that several subunits of the polybromo-associated BAF (PBAF) chromatin remodeling complex, particularly Brd7, are required for maintaining breast metastatic dormancy lungs female mice. Brd7 loss induces reawakening, along with modifications epigenomic landscapes and upregulated oncogenic signaling. Breast cells harboring inactivation also reprogram surrounding immune microenvironment downregulating MHC-1 expression promoting a pro-metastatic cytokine profile. Flow cytometric single-cell analyses reveal increased levels pro-tumorigenic inflammatory transitional neutrophils, CD8+ exhausted T cells, CD4+ stress response from mice Brd7-deficient metastases. Finally, attenuating this immunosuppressive milieu neutrophil depletion, extracellular trap (NET) inhibition, or checkpoint therapy abrogates outgrowth. These findings implicate PBAF triggering outgrowth cancer, pointing to targetable underlying mechanisms involving specific cell compartments. Metastasis-initiating can reawaken dormant state initially allowed them survive, Here, authors show promotes tumor drives reawakening lung.

Язык: Английский

Процитировано

2