Spatial immune heterogeneity in a mouse tumor model after immunotherapy DOI Creative Commons
Michal Šmahel,

Shweta Dilip Johari,

Jana Šmahelová

et al.

Cancer Science, Journal Year: 2024, Volume and Issue: unknown

Published: Dec. 3, 2024

Abstract Cancer immunotherapy is increasingly used in clinical practice, but its success rate reduced by tumor escape from the immune system. This may be due to genetic instability of cells, which allows them adapt response and leads intratumoral heterogeneity. The study investigated spatial heterogeneity microenvironment possible drivers a mouse model tumors induced human papillomaviruses (HPV) following immunotherapy. Gene expression was determined RNA sequencing mutations whole exome sequencing. A comparison different areas revealed cell infiltration, gene expression, mutation composition. While mean numbers with every impact on or protein function were comparable treated control tumors, high moderate increased after genes mutated significantly enriched associated ECM metabolism, degradation, interactions, HPV infection carcinogenesis, processes such as antigen processing presentation, Toll‐like receptor signaling, cytokine production. analysis DNA damage repair factors that upregulated Apobec1 Apobec3 downregulated related homologous recombination translesion synthesis. In conclusion, this describes heterogeneity, could lead escape, suggests potential mechanisms involved.

Language: Английский

Mediating Mendelian randomization in the proteome identified potential drug targets for obesity-related allergic asthma DOI Creative Commons

Jiannan Lin,

Shuwen Lu, Xiaoyu Zhao

et al.

Hereditas, Journal Year: 2025, Volume and Issue: 162(1)

Published: Feb. 1, 2025

With the development of economy, number obese patients has been increasing annually worldwide. The proportion asthma associated with obesity is also gradually rising. However, pathogenesis obesity-related remains incompletely understood, and conventional pharmacological treatments generally show limited efficacy. This study aims to explore causal relationship between allergic asthma, elucidate identify plasma proteins involved in its development, providing new insights for clinical interventions. In this study, we employed a two-step approach mediation Mendelian randomization (MR) analysis, utilizing stringent selection criteria instrumental variables (IVs). was used assess impact on validate identified as mediating factors. We further explored functions enriched pathways using Gene Ontology (GO) Kyoto Encyclopedia Genes Genomes (KEGG) analyses. Finally, conducted drug-targeted MR analysis evaluate potential each mediator drug target gene. If significant heterogeneity remained among IVs, applied weighted median method primary analytical tool. Otherwise, utilized inverse variance (IVW) main approach. Additionally, various sensitivity analyses statistical tests illustrate robustness observed associations. research findings indicate asthma. Plasma such TPST1, ROR1, DAPK1 mediate relationship, TPST1 accounting over 10% effect. GO KEGG that genes corresponding these are primarily related responses stimuli, carbohydrate synthesis metabolism, regulation certain protein activities, synaptic connections. suggests SIGLEC12, BOLA1, HOMER2, all have be genes. defined by BMI may promote influencing expression DAPK1. Furthermore, some proteins, including could potentially serve therapeutic targets treating patients. needed their mechanisms underlying effects. Not applicable.

Language: Английский

Citations

0
Versican binds collagen via its G3 domain and regulates the organization and mechanics of collagenous matrices DOI Creative Commons

Dongning Chen,

Yu Du, Jessica Llewellyn

et al.

Journal of Biological Chemistry, Journal Year: 2024, Volume and Issue: 300(12), P. 107968 - 107968

Published: Nov. 5, 2024

Language: Английский

Citations

3
Stromal Versican Accumulation and Proteolysis Regulate the Infiltration of CD8+ T Cells in Breast Cancer DOI Open Access

Philip B. Emmerich,

Tonela Qyli,

Katherine A. Johnson

et al.

Cancers, Journal Year: 2025, Volume and Issue: 17(9), P. 1435 - 1435

Published: April 25, 2025

Background/Objectives: Recent clinical trials in breast cancer have demonstrated that some patients benefit from immune checkpoint blockade, though better predictive markers are needed. The accumulation of the immunomodulatory matrix proteoglycan versican (VCAN) can predict exclusion CD8+ tumor-infiltrating lymphocytes (TILs) settings and, thus, is evaluated here. Methods: A total 230 cancers were analyzed for VCAN accumulation, proteolysis, and TILs. TILs categorized based on their localization tumor epithelial or stromal compartments. Results: was detected 90% cancers, more commonly ER+ tumors (93% vs. 77%; p < 0.001). MCF7 cells treated with estrogen upregulate without an enhanced expression ADAMTS-proteases. VCAN-undetectable demonstrate greater compared to VCAN-detectable (p = 0.012). T within TNBC high proteolysis infiltrated compartment often than low (91% 42% respectively; 0.008). In TCGA cohort, a strong inverse correlation between CD8A observed across subtypes. Conclusions: correlates subtypes cancer, warranting further validation as biomarkers immunotherapy.

Language: Английский

Citations

0
Soluble Proteoglycans and Proteoglycan Fragments as Biomarkers of Pathological Extracellular Matrix Remodeling DOI Creative Commons
Marsioleda Kemberi, Alexander Frederick Minns, Salvatore Santamaria

et al.

Proteoglycan Research, Journal Year: 2024, Volume and Issue: 2(4)

Published: Oct. 1, 2024

Proteoglycans and their proteolytic fragments diffuse into biological fluids such as plasma, serum, urine, or synovial fluid, where they can be detected by antibodies mass-spectrometry. Neopeptides generated the proteolysis of proteoglycans are recognized specific neoepitope act a proxy for activity certain proteases. Proteoglycan proteoglycan potentially used prognostic, diagnostic, theragnostic biomarkers several diseases characterized dysregulated extracellular matrix remodeling osteoarthritis, rheumatoid arthritis, atherosclerosis, thoracic aortic aneurysms, central nervous system disorders, viral infections, cancer. Here, we review main mechanisms accounting presence soluble in fluids, potential application biomarkers, highlight challenges opportunities ahead clinical translation.

Language: Английский

Citations

2
Drivers of Spatial Immune Heterogeneity in a Mouse Tumor Model after Immunotherapy DOI
Michal Šmahel,

Shweta Dilip Johari,

Jana Šmahelová

et al.

Published: Jan. 1, 2024

Language: Английский

Citations

0
Tumour’s Digest: Macrophage metabolism creates a barrier to T cells DOI
Eleanor J. Tyler, Oliver M.T. Pearce

Cancer Research, Journal Year: 2024, Volume and Issue: 84(20), P. 3322 - 3323

Published: Aug. 26, 2024

Changes in the composition and physical properties of tumor extracellular matrix are linked to poor cytotoxic T-cell infiltration therapy response, yet underlying mechanisms remain unclear. Tharp colleagues revealed a fascinating cascade where fibrosis alters macrophage metabolism, restricting nutrients available infiltrating T cells resulting their suppression exclusion from microenvironment. This study suggests that targeting metabolic pathways could be promising strategy overcome immune induced by matrix.

Language: Английский

Citations

0
Spatial immune heterogeneity in a mouse tumor model after immunotherapy DOI Creative Commons
Michal Šmahel,

Shweta Dilip Johari,

Jana Šmahelová

et al.

Cancer Science, Journal Year: 2024, Volume and Issue: unknown

Published: Dec. 3, 2024

Abstract Cancer immunotherapy is increasingly used in clinical practice, but its success rate reduced by tumor escape from the immune system. This may be due to genetic instability of cells, which allows them adapt response and leads intratumoral heterogeneity. The study investigated spatial heterogeneity microenvironment possible drivers a mouse model tumors induced human papillomaviruses (HPV) following immunotherapy. Gene expression was determined RNA sequencing mutations whole exome sequencing. A comparison different areas revealed cell infiltration, gene expression, mutation composition. While mean numbers with every impact on or protein function were comparable treated control tumors, high moderate increased after genes mutated significantly enriched associated ECM metabolism, degradation, interactions, HPV infection carcinogenesis, processes such as antigen processing presentation, Toll‐like receptor signaling, cytokine production. analysis DNA damage repair factors that upregulated Apobec1 Apobec3 downregulated related homologous recombination translesion synthesis. In conclusion, this describes heterogeneity, could lead escape, suggests potential mechanisms involved.

Language: Английский

Citations

0