Reversing NK cell exhaustion: a novel strategy combining immune checkpoint blockade with drug sensitivity enhancement in the treatment of hepatocellular carcinoma

Frontiers in Oncology, Journal Year: 2025, Volume and Issue: 14

Published: Jan. 21, 2025

Hepatocellular carcinoma (HCC) is one of the most common lethal cancers worldwide. Natural killer cells (NK cells) play a key role in liver immunosurveillance, but tumor microenvironment, NK are readily depleted, as evidenced by down-regulation activating receptors, reduced cytokine secretion, and attenuated killing function. The up-regulation inhibitory such PD-1, TIM-3, LAG-3, further exacerbates depletion cells. Combined blockade strategies targeting these immunosuppressive mechanisms, combination PD-1 inhibitors with other pathways (eg. TIM-3 LAG-3), have shown potential to reverse cell exhaustion preclinical studies. This article explores promise innovative HCC immunotherapy, providing new therapeutic directions for optimizing function improving drug sensitivity.

Language: Английский

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Current advancement of immune function paradox of tumour-infiltrating cells and their immunotherapeutic targets: a mini-review

Naunyn-Schmiedeberg s Archives of Pharmacology, Journal Year: 2025, Volume and Issue: unknown

Published: March 10, 2025

Language: Английский

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TIM-3 teams up with PD-1 in cancer immunotherapy: mechanisms and perspectives

Molecular Biomedicine, Journal Year: 2025, Volume and Issue: 6(1)

Published: May 7, 2025

Abstract Immunotherapy using immune checkpoint inhibitors (ICIs) has become a prominent strategy for cancer treatment over the past ten years. However, efficacy of ICIs remains limited, with certain cancers exhibiting resistance to these therapeutic approaches. Consequently, several proteins are presently being thoroughly screened and assessed in both preclinical clinical studies. Among candidates, T cell immunoglobulin mucin-domain containing-3 (TIM-3) is considered promising target. TIM-3 exhibits multiple immunosuppressive effects on various types cells. Given its differential expression levels at distinct stages dysfunction tumor microenvironment (TME), TIM-3, along programmed death protein 1 (PD-1), serves as indicators exhaustion. Moreover, it crucial carefully evaluate impact PD-1 cells immunotherapy. To increase effectiveness anti-TIM-3 anti-PD-1 therapies, proposed combine inhibition PD-1, death-ligand (PD-L1). The conjunction PD-1/PD-L1 evaluated number ongoing trials patients cancers. This study systematically investigates fundamental biology well detailed mechanisms through which axis contribute evasion. Additionally, this article provides thorough analysis evaluating synergistic combining anti-cancer treatment, an overview current status antibodies.

Language: Английский

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Phenotype and function of IL-10–producing NK cells in individuals with malaria experience

JCI Insight, Journal Year: 2025, Volume and Issue: 10(9)

Published: May 7, 2025

P.falciparum infection can trigger high levels of inflammation that lead to fever and sometimes severe disease. People living in malaria-endemic areas gradually develop resistance symptomatic malaria control both parasite numbers the inflammatory response. We previously found adaptive NK cells correlated with reduced load protection from symptoms. also murine cell production IL-10 protected mice experimental cerebral malaria. Human secrete IL-10, but it is unknown what subsets produce or if this affected by experience. hypothesized immunoregulation may lower reduce induction. Here, we showed participants experience make significantly more than no then determined proportions are cytotoxic IFN-γ and/or identified a signature checkpoint molecules on IL-10-producing cells. Lastly, coculture primary monocytes, Plasmodium-infected RBCs, antibody induced These data suggest contribute symptoms via production.

Language: Английский

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TOX2 nuclear-cytosol translocation is linked to leukemogenesis of acute T-cell leukemia by repressing TIM3 transcription

Cell Death and Differentiation, Journal Year: 2024, Volume and Issue: 31(11), P. 1506 - 1518

Published: July 30, 2024

Abstract Nuclear factors TOX and TOX2 upregulate TIM3 expression lead to T-cell exhaustion in malignancies. Here, we demonstrate two distinct patterns (high & low) with high levels acute lymphoblastic leukemia (T-ALL) specimens cell lines. However, the mechanisms regulated by signaling leukemogenesis are unclear. We found that proteins each directly upregulated HAVCR2 transcription, while cellular localization of was different Jurkat MOLT3 cells (nucleus) T2 normal T (cytoplasm). formed a protein complex repressed promoter activity recruiting transcriptional corepressor LCOR deacetylase HDAC3. The nuclear-cytosol translocation deacetylation-dependent cooperatively mediated Sirt1 kinase TBK1. Radiation damage induced nuclear decreased Sirt1, TIM3, caspase 1 cells. Accordingly, knockdown TOX, or LCOR; HDAC3 inhibition; overexpression apoptosis vitro slow growth vivo. Thus, our findings novel regulatory mechanism involving TOX-TOX2 pathway T-ALL.

Language: Английский

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Reduced T and NK Cell Activity in Glioblastoma Patients Correlates with TIM-3 and BAT3 Dysregulation

Cells, Journal Year: 2024, Volume and Issue: 13(21), P. 1777 - 1777

Published: Oct. 26, 2024

Inhibitory receptors are critical for regulating immune cell function. In cancer, these often over-expressed on the surface of T and NK cells, leading to reduced anti-tumor activity. Here, through analysis 11 commonly studied checkpoint inhibitory receptors, we discern that only

Language: Английский

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Immune-mediated liver injury from checkpoint inhibitors: mechanisms, clinical characteristics and management

Nature Reviews Gastroenterology & Hepatology, Journal Year: 2024, Volume and Issue: unknown

Published: Dec. 11, 2024

Language: Английский

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β-Catenin in Dendritic Cells Negatively Regulates CD8 T Cell Immune Responses through the Immune Checkpoint Molecule Tim-3

Vaccines, Journal Year: 2024, Volume and Issue: 12(5), P. 460 - 460

Published: April 25, 2024

Recent studies have demonstrated that β-catenin in dendritic cells (DCs) serves as a key mediator promoting both CD4 and CD8 T cell tolerance, although the mechanisms underlying how exerts its functions remain incompletely understood. Here, we report activation of leads to up-regulation inhibitory molecule T-cell immunoglobulin mucin domain 3 (Tim-3) type 1 conventional DCs (cDC1s). Using cDC1-targeted vaccine model with anti-DEC-205 engineered express melanoma antigen human gp100 (anti-DEC-205-hgp100), CD11c-β-cateninactive mice exhibited impaired cross-priming memory responses gp100-specific (Pmel-1) upon immunization anti-DEC-205-hgp100. Single-cell RNA sequencing (scRNA-seq) analysis revealed negatively regulated transcription programs for effector function proliferation primed Pmel-1 cells, correlating suppressed immunity mice. Further experiments showed treating an anti-Tim-3 antibody anti-DEC-205-hgp100 vaccination led restored suggesting treatment likely synergizes DC vaccines improve their efficacy. Indeed, B16F10-bearing using combination resulted significantly reduced tumor growth compared alone. Taken together, identified β-catenin/Tim-3 axis potentially novel mechanism inhibit anti-tumor immunotherapy DC-targeted improved

Language: Английский

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Role of TIM-3 in ovarian cancer: the forsaken cop or a new noble

Frontiers in Immunology, Journal Year: 2024, Volume and Issue: 15

Published: Aug. 13, 2024

T cell immunoglobulin and mucin domain-3 (TIM-3), a crucial immune checkpoint following PD1 CTLA4, is widely found in several cells. Nonetheless, its performance recent clinical trials appears disappointing. Ovarian cancer (OC), malignant tumor with high mortality rate gynecology, faces significant hurdles immunotherapy. The broad presence of TIM-3 offers new opportunity for immunotherapy OC. This study reviews the role OC assesses potential as target regulatory effects on microenvironment are discussed, focus preclinical studies that demonstrate TIM-3’s modulation various cells Additionally, therapeutic advantages challenges targeting examined.

Language: Английский

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Exploring Gene-Mediated Mechanisms Behind Shared Phenotypes Across Diverse Diseases Using the clGENE Tool

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: April 12, 2024

Abstract The observation of similar clinical characteristics across a broad spectrum diseases suggests the existence underlying shared molecular mechanisms. Identifying these mechanisms is critical for uncovering roots and advancing development innovative therapeutic strategies. However, researching common genes that mediate phenotypes among different often requires integration various sequencing datasets data. batch effects complexity data present significant challenges to research. This study developed framework named “clGENE”, aimed at behind diseases. By integrating normalization, cosine similarity analysis, principal component analysis (PCA) algorithms, this capable effectively identifying associated with specific further selecting key genes. Through pan-cancer dataset, we have verified efficacy reliability “clGENE” framework. Furthermore, also established dataset on immune cell infiltration successfully identified patterns in cancer lymph node metastasis stages using ‘clGENE’ framework, confirming its potential application biomedical

Language: Английский

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