Tertiary lymphoid structures in diseases: immune mechanisms and therapeutic advances

Signal Transduction and Targeted Therapy, Год журнала: 2024, Номер 9(1)

Опубликована: Авг. 28, 2024

Tertiary lymphoid structures (TLSs) are defined as aggregates formed in non-hematopoietic organs under pathological conditions. Similar to secondary (SLOs), the formation of TLSs relies on interaction between tissue inducer (LTi) cells and organizer (LTo) cells, involving multiple cytokines. Heterogeneity is a distinguishing feature TLSs, which may lead differences their functions. Growing evidence suggests that associated with various diseases, such cancers, autoimmune transplant rejection, chronic inflammation, infection, even ageing. However, detailed mechanisms behind these clinical associations not yet fully understood. The by TLS maturation localization affect immune function also unclear. Therefore, it necessary enhance understanding development at cellular molecular level, allow us utilize them improve microenvironment. In this review, we delve into composition, mechanism, potential therapeutic applications TLSs. Furthermore, discuss implications role markers response prognosis. Finally, summarize methods for detecting targeting Overall, provide comprehensive aim develop more effective strategies.

Язык: Английский

---

Role of tertiary lymphoid structures and B cells in clinical immunotherapy of gastric cancer

Frontiers in Immunology, Год журнала: 2025, Номер 15

Опубликована: Янв. 7, 2025

Gastric cancer is a common malignant tumor of the digestive tract, and its treatment remains significant challenge. In recent years, role various immune cells in microenvironment progression has gained increasing attention. Immunotherapy, primarily based on checkpoint inhibitors, notably improved prognosis patients with gastric cancer; however, challenges regarding therapeutic efficacy persist. Histological features within microenvironment, such as tertiary lymphoid structures (TLSs), tumor-infiltrating lymphocytes, proportion intratumoral stroma, are emerging potentially effective prognostic factors. cancer, TLSs may serve local hubs, enhancing ability to interact recognize antigens, which closely linked effectiveness immunotherapy survival rates patients. However, specific cell type driving TLS formation tumors not yet been elucidated. Mature B-cell regions containing germinal centers. During center formation, B undergo transformations become mature function, exerting anti-tumor effects. Therefore, targeting could provide new avenues for immunotherapy. This review, combined current research elaborates relationship between aiming guidance precise

Язык: Английский

---

Exploring effects of gut microbiota on tertiary lymphoid structure formation for tumor immunotherapy

Frontiers in Immunology, Год журнала: 2025, Номер 15

Опубликована: Март 7, 2025

Anti-tumor immunity, including innate and adaptive immunity is critical in inhibiting tumorigenesis development of tumor. The needs specific lymph organs such as tertiary lymphoid structures (TLSs), which are highly correlated with improved survival outcomes many cancers. In recent years, increasing attention on the TLS tumor microenvironment, TLSs have emerged a novel target for anti-tumor therapy. Excitingly, studies shown contribution to immune responses. However, it unclear how form more effectively defense against through formation. Recent that inflammation plays role Interestingly, also found gut microbiota can regulate occurrence inflammation. Therefore, we here summarize potential effects microbiota- mediated or immunosuppression formation environments. Meanwhile, this review explores manipulate mature regulating microbiota/metabolites associated signal pathways potentially lead next-generation cancer immunotherapy.

Язык: Английский

---

Mitophagy and clear cell renal cell carcinoma: insights from single-cell and spatial transcriptomics analysis

Frontiers in Immunology, Год журнала: 2024, Номер 15

Опубликована: Июнь 27, 2024

Background Clear Cell Renal Carcinoma (ccRCC) is the most common type of kidney cancer, characterized by high heterogeneity and complexity. Recent studies have identified mitochondrial defects autophagy as key players in development ccRCC. This study aims to delve into changes mitophagic activity within ccRCC its impact on tumor microenvironment, revealing role cell metabolism, development, survival strategies. Methods Comprehensive analysis tissues using single sequencing spatial transcriptomics reveal mitophagy Mitophagy was determined be altered among renal clear cells gene set scoring. Key populations prognostic genes were NMF approaches. The UBB also demonstrated vitro experiments. Results Compared normal tissue, various types exhibited significantly increased levels mitophagy, especially cells. associated with levels, such UBC, UBA52, TOMM7, UBB, MAP1LC3B, CSNK2B, identified, their expression closely linked poor patient prognosis. Particularly, ubiquitination process involving found crucial for quality control. Conclusion highlights central regulatory factors ccRCC, significance disease progression.

Язык: Английский

---

The pathogenesis and therapeutic implications of metabolic reprogramming in renal cell carcinoma

Cell Death Discovery, Год журнала: 2025, Номер 11(1)

Опубликована: Апрель 19, 2025

Abstract Renal cell carcinoma (RCC), a therapeutically recalcitrant genitourinary malignancy, exemplifies the profound interplay between oncogenic signaling and metabolic adaptation. Emerging evidence positions reprogramming as central axis of RCC pathogenesis, characterized by dynamic shifts in nutrient utilization that transcend canonical Warburg physiology to encompass lipid anabolism, glutamine auxotrophy, microenvironment-driven plasticity. This orchestrated rewiring cellular energetics sustains tumor proliferation under hypoxia while fostering immunosuppression through metabolite-mediated T exhaustion myeloid-derived suppressor activation. Crucially, exhibits heterogeneity across histological subtypes intratumoral regions—a feature increasingly recognized determinant therapeutic resistance. Our review systematically deciphers molecular architecture metabolism, elucidating how VHL/HIF mutations, mTOR pathway dysregulation, epigenetic modifiers converge reshape glucose flux, droplet biogenesis, amino acid catabolism. We present novel insights into spatial zonation within tumors, where pseudohypoxic niches engage lactate shuttling cholesterol efflux adjacent vasculature, creating pro-angiogenic immunosuppressive microdomains. Therapeutically, we evaluate first-in-class inhibitors targeting rate-limiting enzymes de novo lipogenesis proposing biomarker-driven strategies overcome compensatory highlight synergy glutaminase PD-1 blockade reinvigorating CD8 + function, role lipid-loaded cancer-associated fibroblasts shielding tumors from ferroptosis. Finally, outline translational roadmap integrating multi-omics profiling, functional metabolomics, biology match vulnerabilities with precision therapies.

Язык: Английский

---

Density of tertiary lymphoid structures predicts clinical outcome in breast cancer brain metastasis

Journal for ImmunoTherapy of Cancer, Год журнала: 2024, Номер 12(7), С. e009232 - e009232

Опубликована: Июль 1, 2024

Background Patients with breast cancer brain metastases (BCBM) experience a rapid decline in their quality of life. Recently, tertiary lymphoid structures (TLSs), analogs secondary organs, have attracted extensive attention. However, the potential clinical implications TLSs BCBMs are poorly understood. In this study, we evaluated density and composition described prognostic value. Methods Clinicopathological data were collected from 98 patients (2015–2021). evaluated, TLS scoring system was constructed. Differences progression-free survival (PFS) overall (OS) between groups calculated using Kaplan-Meier method. Immunohistochemistry multiplex immunofluorescence (mIF) used to assess heterogeneity. Results identified 47 BCBM. High indicated favorable (OS, p=0.003; PFS, p<0.001). positively associated OS (p=0.0172) PFS (p=0.0161) human epidermal growth factor receptor type 2-positive subtype, prolonged (p=0.0482) triple-negative subtype. The mIF results showed significant differences percentages T follicular helper (Tfh) cells, M2 macrophages, cytotoxic lymphocytes, CD8 + TIM-3 lymphocytes scores 0–3 (cytotoxic p=0.044; Tfh, p=0.021; p=0.033; p=0.018). Furthermore, novel nomograms incorporating other clinicopathological predictors demonstrated prominent predictability 1-year, 3-year, 5-year outcomes (area under curve >0.800). Conclusion Our highlight impact abundance on Additionally, immune proposed predict prognosis

Язык: Английский

---

The predictive role of tertiary lymphoid structures in the prognosis and response to immunotherapy of lung cancer patients: a systematic review and meta-analysis

BMC Cancer, Год журнала: 2025, Номер 25(1)

Опубликована: Янв. 15, 2025

There is still no consensus regarding the correlation between TLS and prognosis of lung cancer patients. This meta-analysis aimed to investigate association in patients with cancer. In addition, prognostic value for efficacy immunotherapy was also studied. We systematically searched PubMed, Embase, Cochrane Library, Web Science databases from database inception November 1, 2023. The hazard ratio (HR) corresponding 95% confidence interval (CI) overall survival (OS), disease-free (DFS), recurrence-free (RFS), progression-free (PFS) disease-specific (DSS) were extracted merged STATA 14.0. study protocol registered PROSPERO (CRD42024502483). A total 17 studies comprising 4291 included this meta-analysis. pooled results revealed that high TLS/TLS + had better OS (HR = 0.66, CI: 0.50–0.88), DFS 0.46, 0.33–0.64), DSS 0.48, 0.39–0.60) RFS 0.43, 0.33–0.57). High tended have longer PFS than low 0.68, 0.35–1.35). Interestingly, Asia subgroup, especially significant, whereas there significant difference Europe. who received neoadjuvant chemoimmunotherapy, associated prolonged 0.21, 95%CI: 0.05–0.93). improved an response chemoimmunotherapy patients, suggesting may be a biomarker promising predictive marker chemoimmunotherapy. However, additional original are needed further confirm these findings.

Язык: Английский

---

Multiple mechanisms and applications of tertiary lymphoid structures and immune checkpoint blockade

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

Опубликована: Март 5, 2025

Immune checkpoint blockade (ICB) inhibits tumor immune escape and has significantly advanced therapy. However, ICB benefits only a minority of patients treated may lead to many immune-related adverse events. Therefore, identifying factors that can predict treatment outcomes, enhance synergy with ICB, mitigate events is urgently needed. Tertiary lymphoid structures (TLS) are ectopic tissues arise from the periphery. They have been found be associated better prognosis improved clinical outcomes after TLS help address problems ICB. The multiple mechanisms action between remain unknown. This paper described potential interaction two explored their applications.

Язык: Английский

---

Spatial multi-omics analysis of tumor-stroma boundary cell features for predicting breast cancer progression and therapy response

Frontiers in Cell and Developmental Biology, Год журнала: 2025, Номер 13

Опубликована: Март 26, 2025

Background The tumor boundary of breast cancer represents a highly heterogeneous region. In this area, the interactions between malignant and non-malignant cells influence progression, immune evasion, drug resistance. However, spatial transcriptional profile its role in prognosis treatment response remain unclear. Method Utilizing Cottrazm algorithm, we reconstructed intricate boundaries identified differentially expressed genes (DEGs) associated with these regions. Cell-cell co-positioning analysis was conducted using SpaCET, which revealed key tumor-associated macrophage (TAMs) cancer-associated fibroblasts (CAFs). Additionally, Lasso regression employed to develop body signature (MBS), subsequently validated TCGA dataset for prediction assessment. Results Our research indicates that is characterized by rich reconstruction extracellular matrix (ECM), immunomodulatory regulation, epithelial-to-mesenchymal transition (EMT), underscoring significance progression. Spatial colocalization reveals significant interaction CAFs M2-like (TAM), contributes exclusion MBS score effectively stratifies patients into high-risk groups, survival outcomes exhibiting high scores being significantly poorer. Furthermore, sensitivity demonstrates high-MB tumors had poor chemotherapy strategies, highlighting modulating therapeutic efficacy. Conclusion Collectively, investigate transcription group bulk data elucidate characteristics molecules cancer. CAF-M2 phenotype emerges as critical determinant immunosuppression resistance, suggesting targeting may improve responses. serves novel prognostic tool offers potential strategies guiding personalized approaches

Язык: Английский

---

ACAT1 regulates tertiary lymphoid structures and correlates with immunotherapy response in non–small cell lung cancer

Journal of Clinical Investigation, Год журнала: 2025, Номер 135(7)

Опубликована: Март 31, 2025

Tertiary lymphoid structures (TLS) in the tumor microenvironment (TME) are emerging solid-tumor indicators of prognosis and response to immunotherapy. Considering that tumorigenesis requires metabolic reprogramming subsequent TME remodeling, discovery TLS regulators is expected produce immunotherapeutic targets. To identify such regulators, we constructed a metabolism-focused sgRNA library performed an vivo CRISPR screening orthotopic lung mouse model. Combined with The Cancer Genome Atlas database analysis TLS-related hub genes, found loss Acat1 cells sensitized tumors anti-PD1 treatment, accompanied by increased TME. Mechanistic studies revealed ACAT1 resulted mitochondrial protein hypersuccinylation subsequently enhanced oxidative metabolism, which impeded formation. Elimination ROS NAC or knockdown promoted B cell aggregation construction. Consistently, data from tissue microassays 305 patients cancer showed were more abundant non-small (NSCLC) tissues lower expression. Intratumoral expression was associated poor immunotherapy outcomes NSCLC. In conclusion, our results identified as regulator promising target

Язык: Английский

---