Tertiary lymphoid structural heterogeneity determines tumour immunity and prospects for clinical application

Molecular Cancer, Journal Year: 2024, Volume and Issue: 23(1)

Published: April 6, 2024

Abstract Tertiary lymphoid structures (TLS) are clusters of immune cells that resemble and function similarly to secondary organs (SLOs). While TLS is generally associated with an anti-tumour response in most cancer types, it has also been observed act as a pro-tumour response. The heterogeneity largely determined by the composition tumour-infiltrating lymphocytes (TILs) balance cell subsets within tumour-associated (TA-TLS). TA-TLS varying maturity, density, location may have opposing effects on tumour immunity. Higher maturity and/or higher density often favorable clinical outcomes immunotherapeutic response, mainly due crosstalk between different proportions subpopulations TA-TLS. Therefore, can be used marker predict efficacy immunotherapy checkpoint blockade (ICB). Developing efficient imaging induction methods study crucial for enhancing integration techniques biological materials, including nanoprobes hydrogels, alongside artificial intelligence (AI), enables non-invasive vivo visualization TLS. In this review, we explore dynamic interactions among T B phenotypes contribute structural functional diversity TLS, examining both existing emerging induction, focusing immunotherapies biomaterials. We highlight novel therapeutic approaches being explored aim increasing ICB treatment predicting prognosis.

Language: Английский

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Decoding the spatiotemporal heterogeneity of tumor-associated macrophages

Molecular Cancer, Journal Year: 2024, Volume and Issue: 23(1)

Published: July 27, 2024

Abstract Tumor-associated macrophages (TAMs) are pivotal in cancer progression, influencing tumor growth, angiogenesis, and immune evasion. This review explores the spatial temporal heterogeneity of TAMs within microenvironment (TME), highlighting their diverse subtypes, origins, functions. Advanced technologies such as single-cell sequencing multi-omics have elucidated intricate interactions between other TME components, revealing mechanisms behind recruitment, polarization, distribution. Key findings demonstrate that support vascularization, promote epithelial-mesenchymal transition (EMT), modulate extracellular matrix (ECM) remodeling, etc., thereby enhancing invasiveness metastasis. Understanding these complex dynamics offers new therapeutic targets for disrupting TAM-mediated pathways overcoming drug resistance. underscores potential targeting to develop innovative therapies, emphasizing need further research into characteristics functional roles TME.

Language: Английский

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CCL19-producing fibroblasts promote tertiary lymphoid structure formation enhancing anti-tumor IgG response in colorectal cancer liver metastasis

Cancer Cell, Journal Year: 2024, Volume and Issue: 42(8), P. 1370 - 1385.e9

Published: Aug. 1, 2024

Tertiary lymphoid structures (TLSs) are associated with enhanced immunity in tumors. However, their formation and functions colorectal cancer liver metastasis (CRLM) remain unclear. Here, we reveal that intra- peri-tumor mature TLSs (TLS+) improved clinical outcomes than TLS- Using single-cell-RNA-sequencing spatial-enhanced-resolution-omics-sequencing (Stereo-seq), TLS+ tumors enriched IgG

Language: Английский

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Heterogeneity in tertiary lymphoid structures predicts distinct prognosis and immune microenvironment characterizations of clear cell renal cell carcinoma

Journal for ImmunoTherapy of Cancer, Journal Year: 2023, Volume and Issue: 11(12), P. e006667 - e006667

Published: Dec. 1, 2023

Background Tertiary lymphoid structures (TLS) are organized aggregates of immune cells that develop postnatally in non-lymphoid tissues and associated with pathological conditions. TLS typically comprise B-cell follicles containing encompassed by T- cell zones dendritic cells. The prognostic predictive value the tumor microenvironment (TME) as potential mediators antitumor immunity have gained interest. However, precise relationship between localization maturation clinical outcome their presence clear renal carcinoma (ccRCC) is yet to be elucidated. Methods Immunohistochemistry multispectral fluorescence were used evaluate heterogeneity along TME cell-infiltrating characterizations. A thorough investigation implications 395 patients ccRCC from two independent cohorts was conducted. Associations immunologic activity assessed quantifying infiltration. Results Infiltrated identified 34.2% samples (N=395). These found tumor-proximal, tumor-distal, or both 37.8%, 74.1%, 11.9% TLS-positive cases, respectively. higher proportion early tumor-distal (p=0.016), while tumor-proximal primarily comprised secondary follicle-like (p=0.004). In main study cohort (Fudan University Shanghai Cancer Center, N=290), Kaplan-Meier analyses revealed a significant correlation improved progression-free survival (PFS, p<0.001) overall (OS, p=0.002). Conversely, poor PFS (p=0.02) OS (p=0.021). findings further validated an external validation set 105 ccRCC. Notably, mature (namely TLS, CD23 + germinal center) significantly better outcomes Furthermore, novel nomograms incorporating demonstrated remarkable predictability for 8-year resected (area under curve >0.80). Additionally, enriched primary exhibited programmed death-ligand 1 tumor-associated macrophages levels regulatory T infiltration region, indicative suppressive TME. Conclusion This first time elucidates impact heterogeneities on divergent reveal most located area immature, immunosuppressive our corroborate previous research demonstrating favorable outcomes.

Language: Английский

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Unveiling the impact of tertiary lymphoid structures on immunotherapeutic responses of clear cell renal cell carcinoma

MedComm, Journal Year: 2024, Volume and Issue: 5(1)

Published: Jan. 1, 2024

Abstract Tertiary lymphoid structures (TLS) are organized aggregates of immune cells that form under pathological conditions. However, the predictive value TLS in clear cell renal carcinoma (ccRCC) for immunotherapies remains unclear. We comprehensively assessed implications prognosis and immunological responses spatial maturation heterogeneity 655 ccRCC patients. A higher proportion early‐TLS was found peritumoral TLS, while intratumoral mainly comprised secondary follicle‐like (SFL‐TLS), indicating markedly better survival. Notably, presence especially SFL‐TLS, significantly correlated with survival objective reflection rate patients receiving anti‐Programmed Cell Death Protein‐1 (PD‐1)/Programmed Death‐Ligand‐1 (PD‐L1) immunotherapies. In cluster, primary tumor‐associated macrophages, Treg infiltration regions increased prominently, suggesting an immunosuppressive tumor microenvironment. Interestingly, transcriptome annotation multispectral fluorescence showed abundance mature plasma within has capacity to produce IgA IgG, which demonstrate response rates a superior subjected immunotherapy. conclusion, this study revealed on status clinical responses, allowing improvement precise ccRCC.

Language: Английский

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Tertiary lymphoid structures in diseases: immune mechanisms and therapeutic advances

Signal Transduction and Targeted Therapy, Journal Year: 2024, Volume and Issue: 9(1)

Published: Aug. 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.

Language: Английский

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CD74 is associated with inflamed tumor immune microenvironment and predicts responsiveness to PD-1/CTLA-4 bispecific antibody in patients with solid tumors

Cancer Immunology Immunotherapy, Journal Year: 2024, Volume and Issue: 73(2)

Published: Jan. 27, 2024

Abstract Introduction Cadonilimab (AK104) is a first-in-class tetravalent bispecific antibody that targets both PD-1 and CTLA-4, showing manageable safety profile favorable clinical benefits. This study aimed to identify the biomarkers of response explore immune within tumor microenvironment upon AK104 therapy in advanced solid tumors. Material methods Gene expression profiles paired pre- post-treatment tissues from twenty-one patients were analyzed. The association gene levels with either efficacy or prognosis was evaluated subsequently validated published datasets using log-rank for Kaplan–Meier estimates. Comparative analyses before after treatment conducted. visualization tumor-infiltrating lymphocytes performed multiplex immunohistochemistry. predictive value CD74 further protein by Results Baseline associated patient outcomes (overall survival [OS], HR = 0.33, 95% CI 0.11–1.03, p 0.0463), which confirmed datasets. Tumors high at baseline more likely exhibit an immune-inflamed microenvironment. efficiently enhanced infiltration cells Additionally, (≥ 10% area occupied stained cells) better progressive-free (HR 0.21, 0.06–0.68, 0.0065) OS 0.35, 0.12–1.08, 0.0615). Conclusions Our findings demonstrate promising biomarker therapeutic Trial registration number NCT03261011.

Language: Английский

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Artificial intelligence-based spatial analysis of tertiary lymphoid structures and clinical significance for endometrial cancer

Cancer Immunology Immunotherapy, Journal Year: 2025, Volume and Issue: 74(3)

Published: Feb. 1, 2025

Abstract With the incorporation of immune checkpoint inhibitors into treatment endometrial cancer (EC), a deeper understanding tumor microenvironment is critical. Tertiary lymphoid structures (TLSs) are considered favorable prognostic factors for EC, but significance their spatial distribution remains unclear. B cell receptor repertoire analysis performed using six TLS samples located at various distances from showed that TLSs in distal areas had more shared clones with tumor-infiltrating lymphocytes. To comprehensively investigate TLSs, we developed an artificial intelligence model to detect and determine locations whole-slide images. Our effectively quantified were detected 69% patients EC. We identified them as proximal or margin demonstrated (dTLSs) significantly prolonged overall survival progression-free (PFS) across multiple cohorts [hazard ratio (HR), 0.56; 95% confidence interval (CI), 0.36–0.88; p = 0.01 survival; HR, 0.58; CI, 0.40–0.84; 0.004 PFS]. When analyzed by molecular subtype, dTLSs copy-number-high EC subtype longer PFS (HR, 0.51; 0.29–0.91; 0.02). Moreover, higher response rate (87.5 vs. 41.7%) trend toward improved PFS. findings indicate functions implications may vary locations, serve predictors efficacy. This facilitate personalized therapy

Language: Английский

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Distinct maturity and spatial distribution of tertiary lymphoid structures in head and neck squamous cell carcinoma: implications for tumor immunity and clinical outcomes

Cancer Immunology Immunotherapy, Journal Year: 2025, Volume and Issue: 74(3)

Published: Feb. 11, 2025

Language: Английский

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

Journal for ImmunoTherapy of Cancer, Journal Year: 2024, Volume and Issue: 12(7), P. e009232 - e009232

Published: July 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

Language: Английский

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