Single-cell RNA sequencing highlights the role of distinct natural killer subsets in amyotrophic lateral sclerosis DOI Creative Commons

Esther Álvarez‐Sánchez,

Álvaro Carbayo,

Natalia Valle‐Tamayo

и другие.

Research Square (Research Square), Год журнала: 2024, Номер unknown

Опубликована: Дек. 17, 2024

Abstract Background Neuroinflammation plays a major role in amyotrophic lateral sclerosis (ALS), and cumulative evidence suggests that systemic inflammation the infiltration of immune cells into brain contribute to this process. However, no study has investigated peripheral blood ALS pathophysiology using single-cell RNA sequencing (scRNAseq). Methods We aimed characterize from identify ALS-related alterations at resolution. For purpose, mononuclear (PBMC) were isolated 14 patients cognitively unimpaired healthy individuals (HC), matched by age gender, cryopreserved until library preparation scRNAseq. analyzed differences proportions PBMC, gene expression, cell-cell communication patterns with compared HC, their association plasma neurofilament light (NfL) concentrations, surrogate biomarker for neurodegeneration. Flow cytometry was used validate cell type proportions. Results identified expansion CD56dim natural killer (NK) (fold change = 2; adj. p-value 0.0051), which mainly driven NK_2 subpopulation 3.12; 0.0001), mature cytotoxic NK subset. Our results revealed extensive expression cells, pointing towards activation response (adj. 9.2x10− 11) regulation lymphocyte proliferation 6.46x10− 6). changes other such as classical monocytes, distinct CD8 + effector memory T suggested enhanced antigen presentation via histocompatibility class-II 1.23x10− 8) ALS. The inference demonstrated interaction between HLA-E CD94:NKG2C different lymphocytes is unique blood. Finally, regression analysis proportion CD56bright along ALSFRS, disease duration, explained up 76.4% variance NfL levels. Conclusion reveal signature relevant occurring underscore proportion, signaling terminally differentiated (NK_2), well direct

Язык: Английский

Enhancement of anti‐sarcoma immunity by NK cells engineered with mRNA for expression of a EphA2‐targeted CAR DOI Creative Commons
Pui Yeng Lam, Natacha Omer,

J. Wong

и другие.

Clinical and Translational Medicine, Год журнала: 2025, Номер 15(1)

Опубликована: Янв. 1, 2025

Abstract Background Paediatric sarcomas, including rhabdomyosarcoma, Ewing sarcoma and osteosarcoma, represent a group of malignancies that significantly contribute to cancer‐related morbidity mortality in children young adults. These cancers share common challenges, high rates metastasis, recurrence or treatment resistance, leading 5‐year survival rate approximately 20% for patients with advanced disease stages. Despite the critical need, therapeutic advancements have been limited over past three decades. The advent chimeric antigen receptor (CAR)‐based immunotherapies offers promising avenue novel treatments. However, CAR‐T cells faced significant challenges success treating solid tumours due issues such as poor tumour infiltration, immunosuppressive microenvironments off‐target effects. In contrast, adaptation CAR technology natural killer (NK) has demonstrated potential both haematological tumours, suggesting new strategy paediatric sarcomas. Methods This study developed validated CAR‐NK cell therapy targeting ephrin type‐A receptor‐2 (EphA2) antigen, which is highly expressed various Results expression was successfully detected on surface NK post‐electroporation, indicating successful transfection. Significantly, EphA2‐specific enhanced cytotoxic activity against several lines vitro, those compared unmodified cells. Transient messenger RNA (mRNA) transfection safe approach genetic engineering, further chemical modifications mRNA enhancing stability temporal EphA2‐CAR cells, thereby promoting prolonged protein expression. Additionally, vivo EphA2‐CAR‐NK showed anti‐cancer rhabdomyosarcoma osteosarcoma mouse models. Conclusions provides foundational basis clinical evaluation EphA2‐targeted across spectrum anti‐tumour effects observed vitro/vivo suggests improved outcomes hard‐to‐cure Key points Addressing unmet needs Sarcomas. sarcoma, exhibit lack progress decades necessitates innovative approaches. Advancing immunotherapy Natural modified receptors (CARs) overcome limitations particularly tumours. are associated targeting, reduced effects, safety profiles. EphA2 target. EphA2, overexpressed multiple identified viable target CAR‐based its role progression angiogenesis. Innovations mRNA‐based engineering. demonstrates feasibility transient engineer expression, offering non‐integrative safer alternative viral transduction. Enhancements through modifications, can optimise Preclinical efficacy superior cytotoxicity vitro demonstrate models osteosarcoma. Clinical translation potential. findings establish strong preclinical rationale immunotherapeutic option Future research directions: Combining immune checkpoint inhibitors other immunomodulatory agents could enhance durability. Advanced mimicking human needed refine this approach.

Язык: Английский

Процитировано

1
Dysbiosis–NK Cell Crosstalk in Pancreatic Cancer: Toward a Unified Biomarker Signature for Improved Clinical Outcomes DOI Open Access
Sara Fanijavadi, Lars Henrik Jensen

International Journal of Molecular Sciences, Год журнала: 2025, Номер 26(2), С. 730 - 730

Опубликована: Янв. 16, 2025

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer with poor prognosis, primarily due to its immunosuppressive tumor microenvironment (TME), which contributes treatment resistance. Recent research shows that the microbiome, including microbial communities in oral cavity, gut, bile duct, and intratumoral environments, plays a key role PDAC development, imbalances (dysbiosis) promoting inflammation, progression, therapy resistance, side effects. Microbial metabolites can also affect immune cells, especially natural killer (NK) are vital for surveillance, response treatment-related Dysbiosis NK cell function, leading resistance We propose combined biomarker approach, integrating microbiome composition profiles, help predict effects, enabling more personalized therapies. This review examines how dysbiosis dysfunction discusses strategies (e.g., antibiotics, probiotics, vaccines) modulate enhance function. Targeting could activity, improve effectiveness of treatments, reduce However, further needed develop unified cell–microbiome interaction-based biomarkers precise effective patient outcomes.

Язык: Английский

Процитировано

1
Phenotypic Heterogeneity of Dysfunctional Natural Killer Cells During Chronic Infection or Cancer DOI
Kévin Pouxvielh, Marie Marotel, Noëmi Rousseaux

и другие.

Springer eBooks, Год журнала: 2025, Номер unknown, С. 1 - 31

Опубликована: Янв. 1, 2025

Язык: Английский

Процитировано

0
Single-cell RNA sequencing highlights the role of distinct natural killer subsets in sporadic amyotrophic lateral sclerosis DOI Creative Commons

Esther Álvarez‐Sánchez,

Álvaro Carbayo,

Natalia Valle‐Tamayo

и другие.

Journal of Neuroinflammation, Год журнала: 2025, Номер 22(1)

Опубликована: Янв. 23, 2025

Neuroinflammation plays a major role in amyotrophic lateral sclerosis (ALS), and cumulative evidence suggests that systemic inflammation the infiltration of immune cells into brain contribute to this process. However, no study has investigated peripheral blood ALS pathophysiology using single-cell RNA sequencing (scRNAseq). We aimed characterize from identify ALS-related alterations at resolution. For purpose, mononuclear (PBMC) were isolated 14 patients cognitively unimpaired healthy individuals (HC), matched by age gender, cryopreserved until library preparation scRNAseq. analyzed differences proportions PBMC, gene expression, cell-cell communication patterns between HC, as well their association with plasma neurofilament light (NfL) concentrations, surrogate biomarker for neurodegeneration. Flow cytometry was used validate cell type proportions. identified expansion CD56dim natural killer (NK) (fold change = 2; adj. p-value 0.0051), mainly driven specific subpopulation, NK_2 3.12; 0.0001), which represent mature cytotoxic NK subset. Our results revealed extensive expression cells, pointing towards activation response (adj. 9.2 × 10− 11) regulation lymphocyte proliferation 6.46 6). also changes other such classical monocytes, distinct CD8 + effector memory T suggested enhanced antigen presentation via histocompatibility class-II 1.23 8) ALS. The inference demonstrated interaction HLA-E CD94:NKG2C different lymphocytes is unique compared HC. Finally, regression analysis proportion CD56bright along ALSFRS-r, disease duration, explained up 76.4% variance NfL levels. reveal signature relevant occurring underscore proportion, signaling terminally differentiated subpopulation (NK_2), possible

Язык: Английский

Процитировано

0
Natural killer cells occupy unique spatial neighborhoods in HER2- and HER2+ human breast cancers DOI Creative Commons
Femke A. I. Ehlers, Katie E. Blise, Courtney B. Betts

и другие.

Breast Cancer Research, Год журнала: 2025, Номер 27(1)

Опубликована: Янв. 24, 2025

Tumor-infiltrating lymphocytes are considered clinically beneficial in breast cancer, but the significance of natural killer (NK) cells is less well characterized. As increasing evidence has demonstrated that spatial organization immune tumor microenvironments a significant parameter for impacting disease progression as therapeutic responses, an improved understanding tumor-infiltrating NK and their location within contextures needed to improve design effective cell-based therapies. In this study, we developed multiplex immunohistochemistry (mIHC) antibody panel designed quantitatively interrogate leukocyte lineages, focusing on phenotypes, two independent cancer patient cohorts (n = 26 n 30). Owing clinical supporting role HER2+ mediating responses Trastuzumab, further evaluated HER2- specimens separately. Consistent with literature, found CD3+ T were dominant subset across specimens. comparison, cells, identified by CD56 or NKp46 expression, scarce all low granzyme B expression indicating reduced cytotoxic functionality. Whereas cell density phenotype did not appear be influenced HER2 status, analysis revealed distinct phenotypes regarding proximity neoplastic associated status. Spatial cellular neighborhood multiple unique compositions surrounding where from tumors more frequently proximal whereas instead cells. This study establishes utility quantitative mIHC evaluate at single-cell proteomics level illustrates how characteristics neighborhoods vary context cancers.

Язык: Английский

Процитировано

0
Spatial profiling of ANO7 in prostate tissue: links to AR‐signalling‐associated lipid metabolism and inflammation DOI Open Access

Olli Metsälä,

Gudrun Wahlström, Neha Goel

и другие.

The Journal of Pathology, Год журнала: 2025, Номер unknown

Опубликована: Фев. 20, 2025

Prostate cancer (PrCa) is highly prevalent in the Western world. Currently, however, there are many unmet needs PrCa care, for example distinguishing between clinically significant and indolent cases early phases of disease. ANO7 a prostate-specific gene associated with risk prognosis, but its exact function prostate remains unclear. This study investigates role benign prostatic epithelium using spatial transcriptomics by examining differences ANO7-expressing non-expressing epithelial regions their corresponding stromal compartments. A total 18,676 protein-coding genes were assessed from prostatectomy samples collected patients localised cancer. In sample cohort, exhibited distinct, heterogeneous, on-off expression pattern, enabling an in-depth analysis ANO7-dependent processes. ANO7-positive was predominantly enriched luminal cells specific NK cell subtype, CD56bright. contrast, ANO7-negative characterised enrichment club cells, inflammation, features proliferative inflammatory atrophy. Gene-set revealed that androgen receptor (AR) signalling lipid metabolism. detailed differentially expressed identified ANO7- signature, which consisted co-expressed demonstrated high consistency bulk RNA-sequencing (RNA-seq) data. The ANO7-signature AR-regulated genes, highlighted metabolism processes, particularly arachidonic acid metabolism, as key metabolic feature epithelium. Furthermore, clinical significance low-grade PrCa, correlating better response to therapy. summary, these results highlight potential regulating cancer, reinforcing hypothesis functions tumour suppressor. © 2025 Pathological Society Great Britain Ireland.

Язык: Английский

Процитировано

0
Unveiling the immunological landscape: comprehensive characterization of neoantigen-reactive immune cells in neoantigen cancer vaccines DOI Creative Commons
Weijiang Liu, Hong Su, Peng Guo

и другие.

Frontiers in Immunology, Год журнала: 2025, Номер 16

Опубликована: Март 18, 2025

Neoantigen-based cancer vaccine therapy represents a promising precision oncology strategy that targets unique tumor-specific mutations to elicit robust immune response. This therapeutic approach is designed harness the host’s response against neoantigens eliminate cells. The efficacy of neoantigen vaccines dependents on coordinated action diverse cells, including T lymphocytes, dendritic B natural killer and macrophages. Each cell type plays distinct crucial role in recognizing, targeting, destroying malignant Understanding mechanisms governing both individual collective dynamics for success. comprehensive review systematically explores neoantigen-specific their dynamic interactions, clinical application progress, aiming unveil potential value future development treatment.

Язык: Английский

Процитировано

0
Emerging immunotherapies in osteosarcoma: from checkpoint blockade to cellular therapies DOI Creative Commons
Zhiwei Han, Guomin Chen,

Dongchen Wang

и другие.

Frontiers in Immunology, Год журнала: 2025, Номер 16

Опубликована: Март 18, 2025

Osteosarcoma remains a highly aggressive bone malignancy with limited therapeutic options, necessitating novel treatment strategies. Immunotherapy has emerged as promising approach, yet its efficacy in osteosarcoma is hindered by an immunosuppressive tumor microenvironment and resistance mechanisms. This review explores recent advancements checkpoint blockade, cellular therapies, combination strategies aimed at enhancing immune responses. We highlight key challenges, including heterogeneity, poor infiltration, the need for predictive biomarkers. By integrating immunotherapy chemotherapy, radiotherapy, targeted therapy, emerging approaches seek to improve outcomes. provides comprehensive analysis of evolving landscape immunotherapy, offering insights into future directions potential breakthroughs. Researchers clinicians will benefit from understanding these developments, they pave way more effective personalized osteosarcoma.

Язык: Английский

Процитировано

0
Natural killer cells: the immune frontline against circulating tumor cells DOI Creative Commons
Doryan Masmoudi, Martín Villalba, Catherine Alix‐Panabières

и другие.

Journal of Experimental & Clinical Cancer Research, Год журнала: 2025, Номер 44(1)

Опубликована: Апрель 10, 2025

Abstract Natural killer (NK) play a key role in controlling tumor dissemination by mediating cytotoxicity towards cancer cells without the need of education. These are pivotal eliminating circulating (CTCs) from bloodstream, thus limiting spread and metastasis. However, aggressive CTCs can evade NK cell surveillance, facilitating growth at distant sites. In this review, we first discuss biology cells, focusing on their functions within microenvironment (TME), lymphatic system, circulation. We then examine immune evasion mechanisms employed to inhibit activity, including upregulation inhibitory receptors. Finally, explore clinical implications monitoring biomarkers, such as CTCs, for therapeutic decision-making emphasize enhance cell-based therapies overcoming escape mechanisms.

Язык: Английский

Процитировано

0
Considerations for building and using integrated single-cell atlases DOI
Karin Hrovatin, Lisa Sikkema, Vladimir A. Shitov

и другие.

Nature Methods, Год журнала: 2024, Номер unknown

Опубликована: Дек. 13, 2024

Язык: Английский

Процитировано

2