Gfi1 controls the formation of effector-like CD8+ T cells during chronic infection and cancer DOI Creative Commons
Oluwagbemiga A. Ojo, Hongxing Shen,

Jennifer Ingram

et al.

Nature Communications, Journal Year: 2025, Volume and Issue: 16(1)

Published: May 15, 2025

During chronic infection and tumor progression, CD8+ T cells lose their effector functions become exhausted. These exhausted are heterogeneous comprised of progenitors that give rise to effector-like or terminally-exhausted cells. The precise cues mechanisms directing subset formation incompletely understood. Here, we show growth factor independent-1 (Gfi1) is dynamically regulated in LCMV Clone 13 infection, a previously under-described Ly108+CX3CR1+ expresses low levels Gfi1 while other established subsets have high expression. possess distinct chromatin profiles represent transitory develops cells, process dependent on Gfi1. Similarly, tumor-infiltrating required for the terminally differentiated endogenous as well anti-CTLA-induced anti-tumor responses. Taken together, key regulator

Language: Английский

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

et al.

Cell, Journal Year: 2024, Volume and Issue: 187(9), P. 2052 - 2078

Published: April 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.

Language: Английский

Citations

65
CRISPR–Cas9 applications in T cells and adoptive T cell therapies DOI Creative Commons
Xiaoying Chen,

Shuhan Zhong,

Yonghao Zhan

et al.

Cellular & Molecular Biology Letters, Journal Year: 2024, Volume and Issue: 29(1)

Published: April 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.

Language: Английский

Citations

17
Exploring the impact of environmental factors on male reproductive health through epigenetics DOI
Yi Zhang, Jingyan Song, Zhen‐Gao Sun

et al.

Reproductive Toxicology, Journal Year: 2025, Volume and Issue: 132, P. 108832 - 108832

Published: Jan. 6, 2025

Language: Английский

Citations

4
Brd7 loss reawakens dormant metastasis initiating cells in lung by forging an immunosuppressive niche DOI Creative Commons
Jayanta Mondal, Junfeng Zhang,

Qing Feng

et al.

Nature Communications, Journal Year: 2025, Volume and Issue: 16(1)

Published: Feb. 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.

Language: Английский

Citations

2
KLF2 maintains lineage fidelity and suppresses CD8 T cell exhaustion during acute LCMV infection DOI
Eric Fagerberg, John Attanasio, Christine Dien

et al.

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

Citations

2
Chromatin remodellers as therapeutic targets DOI
Hayden A. Malone, Charles W.M. Roberts

Nature Reviews Drug Discovery, Journal Year: 2024, Volume and Issue: 23(9), P. 661 - 681

Published: July 16, 2024

Language: Английский

Citations

12
Distinct epigenomic landscapes underlie tissue-specific memory T cell differentiation DOI

Frank A. Buquicchio,

Raíssa Fonseca, Patrick Yan

et al.

Immunity, Journal Year: 2024, Volume and Issue: 57(9), P. 2202 - 2215.e6

Published: July 22, 2024

Language: Английский

Citations

12
Targeting SWI/SNF Complexes in Cancer: Pharmacological Approaches and Implications DOI Creative Commons

Megan R. Dreier,

Jasmine Walia,

Ivana L. de la Serna

et al.

Epigenomes, Journal Year: 2024, Volume and Issue: 8(1), P. 7 - 7

Published: Feb. 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

Language: Английский

Citations

10
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

et al.

Immunity, Journal Year: 2024, Volume and Issue: 57(8), P. 1780 - 1795.e6

Published: June 5, 2024

Language: Английский

Citations

10
Chromatin Remodelers Are Regulators of the Tumor Immune Microenvironment DOI
Apoorvi Chaudhri, Gregory Lizée, Patrick Hwu

et al.

Cancer Research, Journal Year: 2024, Volume and Issue: 84(7), P. 965 - 976

Published: Jan. 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.

Language: Английский

Citations

9