A Thermosensitive Bi‐Adjuvant Hydrogel Triggers Epitope Spreading to Promote the Anti‐Tumor Efficacy of Frameshift Neoantigens DOI Creative Commons

Yaohua Ke,

Kai Xin, Yaping Tao

и другие.

Advanced Science, Год журнала: 2024, Номер 11(14)

Опубликована: Фев. 2, 2024

Abstract Tumor‐specific frameshift mutations encoding peptides (FSPs) are highly immunogenic neoantigens for personalized cancer immunotherapy, while their clinical efficacy is limited by immunosuppressive tumor microenvironment (TME) and self‐tolerance. Here, a thermosensitive hydrogel (FSP‐RZ‐BPH) delivering dual adjuvants R848 (TLR7/8 agonist) + Zn 2+ (cGAS‐STING designed to promote the of FSPs on murine forestomach (MFC). After peritumoral injection, FSP‐RZ‐BPH behaves as pH‐responsive sustained drug release at sites near effectively transform TME into an inflammatory type. orchestrates innate adaptive immunity activate dendritic cells in tumor‐draining lymph nodes increase number FSPs‐reactive effector memory T ( EM ) 2.9 folds. More importantly, these also exhibit responses nonvaccinated MFC. This epitope spreading effect contributes reduce self‐tolerance maintain long‐lasting anti‐tumor immunity. In MFC suppressive model, achieves 84.8% inhibition rate prolongs survival tumor‐bearing mice with 57.1% complete response rate. As preventive vaccine, can significantly delay growth. Overall, work identifies first time demonstrates bi‐adjuvant effective strategy boost bystander neoantigens.

Язык: Английский

M2 macrophage‑derived exosomes alleviate KCa3.1 channel expression in rapidly paced HL‑1 myocytes via the NF‑κB (p65)/STAT3 signaling pathway DOI Creative Commons

Huiyu Chen,

Huafen Liu, Dishiwen Liu

и другие.

Molecular Medicine Reports, Год журнала: 2024, Номер 29(4)

Опубликована: Фев. 8, 2024

The present study was designed to explore the role of M2 macrophage‑derived exosomes (M2‑exos) on KCa3.1 channel in a cellular atrial fibrillation (AF) model using rapidly paced HL‑1 myocytes. macrophages and M2‑exos were isolated identified. MicroRNA (miR)‑146a‑5p levels quantified reverse transcription‑quantitative PCR (RT‑qPCR). myocytes randomly divided into six groups: Control group, pacing + coculture group (pacing cells cocultured with M2‑exos), mimic‑miR‑146a‑5p NC‑miR‑146a‑5p pyrrolidine dithiocarbamate (PDTC; special blocker NF‑κB signaling pathway) group. Transmission electron microscopy, nanoparticle tracking analysis, western blotting, RT‑qPCR immunohistochemistry performed study. A whole‑cell clamp also applied record current density action potential duration (APD) each results revealed that miR‑146a‑5p highly expressed both M2‑exos. Pacing led shorter APD, an increased higher protein KCa3.1, phosphorylated (p‑)NF‑κB p65, p‑STAT3 IL‑1β compared control M2‑exos, miR‑146a‑5p‑mimic PDTC reduced expression p‑NF‑κB resulting longer APD cells. In conclusion, their cargo, which comprised miR‑146a‑5p, decreased secretion via NF‑κB/STAT3 pathway, limiting caused by rapid pacing.

Язык: Английский

Процитировано

6
Tumor endothelial cell autophagy is a key vascular‐immune checkpoint in melanoma DOI Creative Commons
Jelle Verhoeven, Kathryn Jacobs, Francesca Rizzollo

и другие.

EMBO Molecular Medicine, Год журнала: 2023, Номер 15(12)

Опубликована: Ноя. 27, 2023

Tumor endothelial cells (TECs) actively repress inflammatory responses and maintain an immune-excluded tumor phenotype. However, the molecular mechanisms that sustain TEC-mediated immunosuppression remain largely elusive. Here, we show autophagy ablation in TECs boosts antitumor immunity by supporting infiltration effector function of T-cells, thereby restricting melanoma growth. In melanoma-bearing mice, loss TEC leads to transcriptional expression immunostimulatory/inflammatory phenotype driven heightened NF-kB STING signaling. line, single-cell transcriptomic datasets from patients disclose enriched InflammatoryHigh /AutophagyLow correlation with clinical immunotherapy, responders exhibit increased presence inflamed vessels interfacing infiltrating CD8+ T-cells. Mechanistically, STING-dependent is not critical for immunomodulatory effects ablation, since NF-kB-driven inflammation remains functional STING/ATG5 double knockout TECs. Hence, our study identifies as a principal vascular anti-inflammatory mechanism dampening immunity.

Язык: Английский

Процитировано

14
Key oncogenic signaling pathways affecting tumor-infiltrating lymphocytes infiltration in hepatocellular carcinoma: basic principles and recent advances DOI Creative Commons
Xiang Wang, Zijun Yuan, Zhengbo Li

и другие.

Frontiers in Immunology, Год журнала: 2024, Номер 15

Опубликована: Фев. 15, 2024

The incidence of hepatocellular carcinoma (HCC) ranks first among primary liver cancers, and its mortality rate exhibits a consistent annual increase. treatment HCC has witnessed significant surge in recent years, with the emergence targeted immune therapy as an adjunct to early surgical resection. Adoptive cell (ACT) using tumor-infiltrating lymphocytes (TIL) shown promising results other types solid tumors. This article aims provide comprehensive overview intricate interactions between different TILs their impact on HCC, elucidate strategies for targeting neoantigens through TILs, address challenges encountered TIL therapies along potential solutions. Furthermore, this specifically examines oncogenic signaling pathways activation within tumor microenvironment infiltration dynamics TILs. Additionally, concise is provided regarding preparation techniques update clinical trials investigating TIL-based immunotherapy

Язык: Английский

Процитировано

5
O-GlcNAc of STING mediates antiviral innate immunity DOI Creative Commons
Yujia Li,

Wang An,

Liyuan Lu

и другие.

Cell Communication and Signaling, Год журнала: 2024, Номер 22(1)

Опубликована: Март 1, 2024

Abstract Background O-GlcNAcylation modification affects multiple physiological and pathophysiolocal functions of cells. Altered was reported to participate in antivirus response. Stimulator interferon genes (STING) is an adaptor mediating DNA virus-induced innate immune Whether STING able be modified by how STING-mediated anti-DNA virus response remain unknown. Methods Metabolomics analysis used for detecting metabolic alterations HSV-1 infection Succinylated wheat germ agglutinin (sWGA), co-immunoprecipitation, pull-down assay were employed determining O-GlcNAcylation. Mutagenesis PCR applied the generation mutants. WT Sting1 −/− C57BL/6 mice (KOCMP-72512- -B6NVA) infected with treated inhibitor validating role antiviral Results functionally activated host cells challenged HSV-1. We demonstrated that this signaling event initiated infection-enhanced hexosamine biosynthesis pathway (HBP). (or viral mimics) promotes glucose metabolism a marked increase HBP, which provides donor glucosamine O-GlcNAcylated on threonine 229, led lysine 63-linked ubiquitination activation responses. Mutation T229 alanine abrogated reduced stimulated production (IFN). Application 6-diazo-5-oxonorleucine (DON), agent blocks UDP-GlcNAc inhibits O-GlcNAcylation, markedly attenuated removal wild type mice, leading increased retention, elevated infiltration inflammatory cells, worsened tissue damages those displayed gene knockout mice. Together, our data suggest HSV-1, crucial effective Conclusion activates UDP-Glc-NAc upregulating HBP metabolism. Elevated STING, mediates anti-viral function STING. Targeting could useful strategy immunity.

Язык: Английский

Процитировано

5
A Thermosensitive Bi‐Adjuvant Hydrogel Triggers Epitope Spreading to Promote the Anti‐Tumor Efficacy of Frameshift Neoantigens DOI Creative Commons

Yaohua Ke,

Kai Xin, Yaping Tao

и другие.

Advanced Science, Год журнала: 2024, Номер 11(14)

Опубликована: Фев. 2, 2024

Abstract Tumor‐specific frameshift mutations encoding peptides (FSPs) are highly immunogenic neoantigens for personalized cancer immunotherapy, while their clinical efficacy is limited by immunosuppressive tumor microenvironment (TME) and self‐tolerance. Here, a thermosensitive hydrogel (FSP‐RZ‐BPH) delivering dual adjuvants R848 (TLR7/8 agonist) + Zn 2+ (cGAS‐STING designed to promote the of FSPs on murine forestomach (MFC). After peritumoral injection, FSP‐RZ‐BPH behaves as pH‐responsive sustained drug release at sites near effectively transform TME into an inflammatory type. orchestrates innate adaptive immunity activate dendritic cells in tumor‐draining lymph nodes increase number FSPs‐reactive effector memory T ( EM ) 2.9 folds. More importantly, these also exhibit responses nonvaccinated MFC. This epitope spreading effect contributes reduce self‐tolerance maintain long‐lasting anti‐tumor immunity. In MFC suppressive model, achieves 84.8% inhibition rate prolongs survival tumor‐bearing mice with 57.1% complete response rate. As preventive vaccine, can significantly delay growth. Overall, work identifies first time demonstrates bi‐adjuvant effective strategy boost bystander neoantigens.

Язык: Английский

Процитировано

4