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Introduction: Tertiary lymphoid structures (TLSs) are analogues of secondary lymphoid organs that contain various immune cells. The spatial distribution, maturation and composition of TLSs have differential effects on prognosis, and the roles of TLSs in gastric adenocarcinoma (GA) have not been revealed. Methods: Thus, we evaluated the prognostic value of TLSs in GA through analysis of bulk RNA sequencing(RNA-seq) data from public databases and validated our findings in tumour samples from the Fudan University Shanghai Cancer Center (FUSCC) cohort. The spatial distribution,maturation, and composition of TLSs in GA were analysed by reviewing H&E-stained sections and by multiplex immunofluorescence (mIF) staining. Results: We found that TLSs, especially TLSs with germinal centres (GCs) and TLSs located in the invasive margin (IM), were correlated with prolonged overall survival (OS). Second, analysis of public RNA-seq data showed that high dendritic cell (DC) scores were a favourable prognostic factor in GA patients with high scores for both TLSs and GCs. In the FUSCC cohort, DC-LAMP+ DCs weresignificantly enriched in IM-TLSs with GCs, suggesting a potential correlation between the tumour immune activation milieu and the DC abundance. Third, compared to that in TLSs without GCs, the proportion of FOXP3+CD8+ Treg cells was significantly decreased in IM-TLSs with GCs, and the percentage of PD1+CD20+ B cells was significantly increased in TLSs with GCs. Discussion: Our results demonstrate that the spatial arrangement and maturation of TLSs significantly affect prognosis and indicate that TLSs could be a new additional factor for histopathological evaluation.
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Adenocarcinoma , Neoplasias Gástricas , Estructuras Linfoides Terciarias , Humanos , Neoplasias Gástricas/inmunología , Neoplasias Gástricas/patología , Neoplasias Gástricas/mortalidad , Neoplasias Gástricas/genética , Estructuras Linfoides Terciarias/inmunología , Estructuras Linfoides Terciarias/patología , Adenocarcinoma/inmunología , Adenocarcinoma/mortalidad , Adenocarcinoma/patología , Pronóstico , Masculino , Femenino , Persona de Mediana Edad , Células Dendríticas/inmunología , Anciano , Centro Germinal/inmunología , Centro Germinal/patología , Linfocitos Infiltrantes de Tumor/inmunología , Linfocitos Infiltrantes de Tumor/metabolismo , Microambiente Tumoral/inmunologíaRESUMEN
Tertiary lymphoid structures (TLSs) are associated with enhanced immunity in tumors. However, their formation and functions in colorectal cancer liver metastasis (CRLM) remain unclear. Here, we reveal that intra- and peri-tumor mature TLSs (TLS+) are associated with improved clinical outcomes than TLS- tumors. Using single-cell-RNA-sequencing and spatial-enhanced-resolution-omics-sequencing (Stereo-seq), we reveal that TLS+ tumors are enriched with IgG+ plasma cells (PCs), while TLS- tumors are characterized with IgA+ PCs. By generating TLS-associated PC-derived monoclonal antibodies in vitro, we show that TLS-PCs secrete tumor-targeting antibodies. As the proof-of-concept, we demonstrate the anti-tumor activities of TLS-PC-mAb6 antibody in humanized mouse model of colorectal cancer. We identify a fibroblast lineage secreting CCL19 that facilitates lymphocyte trafficking to TLSs. CCL19 treatment promotes TLS neogenesis and prevents tumor growth in mice. Our data uncover the central role of CCL19+ fibroblasts in TLS formation, which in turn generates therapeutic antibodies to restrict CRLM.
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Quimiocina CCL19 , Neoplasias Colorrectales , Inmunoglobulina G , Neoplasias Hepáticas , Estructuras Linfoides Terciarias , Neoplasias Colorrectales/patología , Neoplasias Colorrectales/inmunología , Neoplasias Colorrectales/metabolismo , Animales , Estructuras Linfoides Terciarias/inmunología , Estructuras Linfoides Terciarias/patología , Humanos , Neoplasias Hepáticas/inmunología , Neoplasias Hepáticas/secundario , Neoplasias Hepáticas/patología , Neoplasias Hepáticas/metabolismo , Ratones , Inmunoglobulina G/inmunología , Quimiocina CCL19/metabolismo , Quimiocina CCL19/genética , Fibroblastos/metabolismo , Fibroblastos/inmunología , Anticuerpos Monoclonales/farmacología , Células Plasmáticas/inmunología , Células Plasmáticas/metabolismo , Femenino , Línea Celular TumoralRESUMEN
Aberrant activation of the cyclic guanosine monophosphate-adenosine monophosphate synthase-stimulator of interferon genes (cGAS-STING) pathway causes autoimmunity in humans and mice; however, the exact mechanism by which the cGAS-STING pathway initiates adaptive immunity and tissue pathology is still not fully understood. Here, we used a cGAS knockin (KI) mouse model that develops systemic autoimmunity. In the lungs of cGAS-KI mice, blood vessels were enclosed by organized lymphoid tissues that resemble tertiary lymphoid structures (TLSs). Cell-intrinsic cGAS induction promoted up-regulation of CCR5 in CD8+ T cells and led to CCL5 production in vascular endothelial cells. Peripheral CD8+ T cells were recruited to the lungs and produced CXCL13 and interferon-γ. The latter triggered endothelial cell death, potentiated CCL5 production, and was essential for TLS establishment. Blocking CCL5 or CCR5, or depleting CD8+ T cells, impaired TLS formation. cGAS-mediated TLS formation also enhanced humoral and antitumor responses. These data demonstrate that cGAS signaling drives a specialized lymphoid structure that underlies autoimmune tissue pathology.
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Linfocitos T CD8-positivos , Células Endoteliales , Nucleotidiltransferasas , Estructuras Linfoides Terciarias , Animales , Nucleotidiltransferasas/inmunología , Nucleotidiltransferasas/genética , Nucleotidiltransferasas/metabolismo , Ratones , Células Endoteliales/inmunología , Estructuras Linfoides Terciarias/inmunología , Linfocitos T CD8-positivos/inmunología , Quimiocina CCL5/inmunología , Quimiocina CCL5/genética , Ratones Endogámicos C57BL , Ratones Transgénicos , Transducción de Señal/inmunología , Receptores CCR5/inmunología , Receptores CCR5/genética , Receptores CCR5/metabolismo , Autoinmunidad/inmunologíaRESUMEN
BACKGROUND: We investigated the feasibility of the tertiary lymphoid structure (TLS) as a prognostic marker for penile squamous cell carcinoma(SCC). METHODS: We retrospectively collected data from 83 patients with penile squamous cell carcinoma. H&E-stained slides were reviewed for TLS density. In addition, clinical parameters were analyzed, the prognostic value of these parameters on overall survival (OS) was evaluated using â Kaplan-Meier survival curves, and the prognostic value of influencing factors was evaluated using Cox multifactor design nomogram analysis. RESULT: BMI, T, N, and M are significant in the survival curve with or without tertiary lymphoid structure. BMI, T, N, M and TLS were used to construct a prognostic model for penile squamous cell carcinoma, and the prediction accuracy reached a consensus of 0.884(0.835-0.932), and the decision consensus reached 0.581(0.508-0.655). CONCLUSION: TLS may be a positive prognostic factor for penile squamous cell carcinoma, and the combination of BMI, T, N and M can better evaluate the prognosis of patients.
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Carcinoma de Células Escamosas , Neoplasias del Pene , Estructuras Linfoides Terciarias , Masculino , Neoplasias del Pene/patología , Neoplasias del Pene/mortalidad , Humanos , Carcinoma de Células Escamosas/patología , Carcinoma de Células Escamosas/mortalidad , Pronóstico , Estudios Retrospectivos , Persona de Mediana Edad , Anciano , Estructuras Linfoides Terciarias/patología , Adulto , Tasa de SupervivenciaRESUMEN
Ectopic lymphoid structures (ELSs) in the rheumatoid synovial joints sustain autoreactivity against locally expressed autoantigens. We recently identified recombinant monoclonal antibodies (RA-rmAbs) derived from single, locally differentiated rheumatoid arthritis (RA) synovial B cells, which specifically recognize fibroblast-like synoviocytes (FLSs). Here, we aimed to identify the specificity of FLS-derived autoantigens fueling local autoimmunity and the functional role of anti-FLS antibodies in promoting chronic inflammation. A subset of anti-FLS RA-rmAbs reacting with a 60 kDa band from FLS extracts demonstrated specificity for HSP60 and partial cross-reactivity to other stromal autoantigens (i.e., calreticulin/vimentin) but not to citrullinated fibrinogen. Anti-FLS RA-rmAbs, but not anti-neutrophil extracellular traps rmAbs, exhibited pathogenic properties in a mouse model of collagen-induced arthritis. In patients, anti-HSP60 antibodies were preferentially detected in RA versus osteoarthritis (OA) synovial fluid. Synovial HSPD1 and CALR gene expression analyzed using bulk RNA-Seq and GeoMx-DSP closely correlated with the lympho-myeloid RA pathotype, and HSP60 protein expression was predominantly observed around ELS. Moreover, we observed a significant reduction in synovial HSP60 gene expression followed B cell depletion with rituximab that was strongly associated with the treatment response. Overall, we report that synovial stromal-derived autoantigens are targeted by pathogenic autoantibodies and are associated with specific RA pathotypes, with potential value for patient stratification and as predictors of the response to B cell-depleting therapies.
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Artritis Reumatoide , Autoantígenos , Chaperonina 60 , Centro Germinal , Artritis Reumatoide/inmunología , Artritis Reumatoide/patología , Animales , Humanos , Ratones , Autoantígenos/inmunología , Autoantígenos/genética , Centro Germinal/inmunología , Centro Germinal/patología , Chaperonina 60/inmunología , Chaperonina 60/genética , Autoanticuerpos/inmunología , Autoinmunidad , Masculino , Sinoviocitos/inmunología , Sinoviocitos/patología , Sinoviocitos/metabolismo , Artritis Experimental/inmunología , Artritis Experimental/patología , Femenino , Linfocitos B/inmunología , Linfocitos B/patología , Estructuras Linfoides Terciarias/inmunología , Estructuras Linfoides Terciarias/patologíaRESUMEN
Immunotherapy shows substantial advancement in cancer and is becoming widely used in clinical practice. A variety of biomarkers have been proposed to predict the efficacy of immunotherapy, but most of them have low predictive ability. Tertiary lymphoid structures (TLSs), the aggregation of multiple lymphocytes, have been found to exist in various tumor tissues. TLSs have been shown to correlate with patient prognosis and immunotherapy response. This review summarizes the characteristics of TLSs and the inducing factors of TLS formation, presents available evidence on the role of TLSs in predicting immunotherapy response in different cancers, and lastly emphasizes their predictive potential for neoadjuvant immunotherapy efficacy.
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Biomarcadores de Tumor , Inmunoterapia , Neoplasias , Estructuras Linfoides Terciarias , Humanos , Estructuras Linfoides Terciarias/inmunología , Inmunoterapia/métodos , Neoplasias/inmunología , Neoplasias/terapia , Animales , Pronóstico , Microambiente Tumoral/inmunologíaRESUMEN
Tertiary lymphoid structures (TLS) represent the ectopic aggregations of immune cells arising during chronic inflammation or tumor progression. In cancer, TLS are often associated with beneficial clinical outcomes in patients undergoing immunotherapy, underscoring their prognostic and predictive significance. Mature TLS, characterized by germinal centers and areas of T-cell and B-cell aggregation, are considered primary locations for activating and maintaining both humoral and cellular anti-tumor immune effects. Despite their recognized importance, the mechanisms driving the formation of mature TLS in cancer and their influence on the immune response within tumors remain insufficiently understood. Therefore, this review aims to comprehensively explore the structural composition, development mechanisms, maturity impact factors, immunological function, and innovative therapeutic strategies of mature TLS within the tumor microenvironment. The research summarized herein offers novel insights and considerations for therapeutic approaches to promote TLS generation and maturation in patients with cancer, representing a promising avenue for future cancer therapies.
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Neoplasias , Estructuras Linfoides Terciarias , Microambiente Tumoral , Humanos , Estructuras Linfoides Terciarias/inmunología , Estructuras Linfoides Terciarias/patología , Neoplasias/inmunología , Neoplasias/terapia , Neoplasias/patología , Microambiente Tumoral/inmunología , Animales , Inmunoterapia/métodos , Linfocitos B/inmunología , Linfocitos T/inmunologíaRESUMEN
BACKGROUND: Non-small cell lung cancer (NSCLC) is the primary reason for cancer-related deaths globally. Tertiary lymphoid structure (TLS) is an organized collection of immune cells acquired in non-physiological, non-lymphoid tissues. High expression of TLS in tumor tissues is generally associated with better prognosis. This research aimed to investigate the prognostic and clinicopathological significance of TLS in patients with NSCLC. METHODS: A comprehensive literature search was conducted based on Pubmed, EMBASE, and Cochrane Library databases to identify eligible studies published up to December 8, 2023. The prognostic significance and clinicopathological value of TLS in NSCLC were evaluated by calculating the combined hazard ratios (HRs) and odds ratios (ORs) and their 95% confidence intervals (CIs). Following that, additional analyses, including subgroup analysis and sensitivity analysis, were conducted. RESULTS: This meta-analysis evaluated the prognostic and clinicopathological significance of TLS in 10 studies involving 1,451 patients with NSCLC. The results revealed that the high levels of TLS were strongly associated with better overall survival (OS) (HR = 0.48, 95% CI: 0.35-0.66, p < 0.001), disease-free survival (DFS)/recurrence-free survival (RFS) (HR = 0.37, 95% CI: 0.24-0.54, p < 0.001), and disease-specific survival (DSS) (HR = 0.45, 95% CI: 0.30-0.68, p < 0.001) in NSCLC patients. In addition, the increased expression of TLS was closely related to the Tumor Node Metastasis (TNM) stage of tumors (OR = 0.71, 95% CI: 0.51-1.00, p < 0.05) and neutrophil-lymphocyte ratio (NLR) (OR = 0.33, 95% CI: 0.17-0.62, p < 0.001). CONCLUSIONS: The results revealed that highly expressed TLS is closely associated with a better prognosis in NSCLC patients. TLS may serve as a novel biomarker to predict the prognosis of NSCLC patients and guide the clinical treatment decisions.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Estructuras Linfoides Terciarias , Carcinoma de Pulmón de Células no Pequeñas/patología , Carcinoma de Pulmón de Células no Pequeñas/mortalidad , Carcinoma de Pulmón de Células no Pequeñas/inmunología , Humanos , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/mortalidad , Neoplasias Pulmonares/inmunología , Pronóstico , Estructuras Linfoides Terciarias/patología , Estructuras Linfoides Terciarias/inmunología , Supervivencia sin Enfermedad , Biomarcadores de Tumor/metabolismoRESUMEN
Background: Although numerous studies have reported the association between tertiary lymphoid structures (TLSs) and clinical outcomes in cancer patients treated with immune checkpoint inhibitors (ICIs), there remains a lack of a newer and more comprehensive meta-analysis. The main objective of this study is to explore prognostic biomarkers in immunotherapy-related patients, through analyzing the associations between tertiary lymphoid structures (TLSs) and clinical outcomes in cancer patients treated with ICIs, so as to investigate their prognostic value in cancer patients treated with ICIs. Methods: A comprehensive search was conducted until February 2024 across PubMed, Embase, Web of Science, and the Cochrane Library databases to identify relevant studies evaluating the association between tertiary lymphoid structures and clinical outcomes in cancer patients treated with ICIs. The clinical outcomes were overall survival (OS), progression-free survival (PFS), and objective response rate (ORR). Results: Thirteen studies were incorporated in this meta-analysis, among which nine evaluated the prognostic value of TLSs. The results showed the high levels of TLSs predicted a significantly prolonged OS (pooled HR = 0.35, 95% CI: 0.24-0.53, p < 0.001) and PFS (pooled HR = 0.47, 95% CI: 0.31-0.72, p < 0.001), while lower ORR (pooled OR = 3.78, 95% CI: 2.26-6.33, p < 0.001) in cancer patients treated with ICIs. Conclusion: Our results indicated that high levels of TLSs could predict a favorable prognosis for cancer patients treated with ICIs and have the potential to become a prognostic biomarker of immunotherapy-related patients.
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Inhibidores de Puntos de Control Inmunológico , Neoplasias , Estructuras Linfoides Terciarias , Humanos , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Inhibidores de Puntos de Control Inmunológico/efectos adversos , Neoplasias/tratamiento farmacológico , Neoplasias/mortalidad , Neoplasias/inmunología , Estructuras Linfoides Terciarias/inmunología , Pronóstico , Resultado del Tratamiento , Biomarcadores de TumorRESUMEN
BACKGROUND/AIM: The prognosis of patients with brain metastases (BMs) originating from lung cancer remains poor, despite advancements in treatment strategies. The role of tertiary lymphoid structures (TLSs) within the tumor immune microenvironment of BMs has not been extensively explored. PATIENTS AND METHODS: This study utilized patient-derived clinical samples from 17 patients with histologically confirmed BMs of lung cancer, undergoing surgical resection. Immunohistochemistry was employed to analyze the presence and characteristics of TLS and tumor-infiltrating lymphocytes (TILs) within BM tissues, correlating these with clinical outcomes. RESULTS: TLSs, albeit in their immature form, were identified within BM tissues, distinguishing them from their mature counterparts in primary lung cancer tissues. A significant correlation between TLS density (but not TIL density) and improved postoperative survival was observed, underscoring the potential of TLS density as an independent prognostic marker. Furthermore, TLS density did not correlate with the Graded Prognostic Assessment (GPA) index, suggesting its unique prognostic value beyond conventional predictors. CONCLUSION: Our findings reveal the presence of TLSs in lung cancer-derived BMs and highlight their prognostic significance, independent of the GPA index. The identification of TLS within the unique central nervous system tumor microenvironment offers new insights into the immune landscape of BMs and suggests potential avenues for immunotherapeutic interventions targeting these structures to improve patient outcomes.
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Neoplasias Encefálicas , Neoplasias Pulmonares , Linfocitos Infiltrantes de Tumor , Estructuras Linfoides Terciarias , Microambiente Tumoral , Humanos , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/inmunología , Neoplasias Pulmonares/mortalidad , Neoplasias Encefálicas/secundario , Neoplasias Encefálicas/inmunología , Estructuras Linfoides Terciarias/inmunología , Estructuras Linfoides Terciarias/patología , Pronóstico , Masculino , Femenino , Persona de Mediana Edad , Microambiente Tumoral/inmunología , Linfocitos Infiltrantes de Tumor/inmunología , AncianoRESUMEN
Solid organ transplantation remains the life-saving treatment for end-stage organ failure, but chronic rejection remains a major obstacle to long-term allograft outcomes and has not improved substantially. Tertiary lymphoid organs (TLOs) are ectopic lymphoid structures that form under conditions of chronic inflammation, and evidence from human transplantation suggests that TLOs regularly form in allografts undergoing chronic rejection. In this study, we utilized a mouse renal transplantation model and manipulation of the lymphotoxin αß/lymphotoxin ß receptor (LTαß/LTßR) pathway, which is essential for TLO formation, to define the role of TLOs in transplantation. We showed that intragraft TLOs are sufficient to activate the alloimmune response and mediate graft rejection in a model where the only lymphoid organs are TLOs in the allograft. When transplanted to recipients with a normal set of secondary lymphoid organs, the presence of graft TLOs or LTα overexpression accelerated rejection. If the LTßR pathway was disrupted in the donor graft, TLO formation was abrogated, and graft survival was prolonged. Intravital microscopy of renal TLOs demonstrated that local T and B cell activation in TLOs is similar to that observed in secondary lymphoid organs. In summary, we demonstrated that immune activation in TLOs contributes to local immune responses, leading to earlier allograft failure. TLOs and the LTαß/LTßR pathway are therefore prime targets to limit local immune responses and prevent allograft rejection. These findings are applicable to other diseases, such as autoimmune diseases or tumors, where either limiting or boosting local immune responses is beneficial and improves disease outcomes.
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Rechazo de Injerto , Trasplante de Riñón , Receptor beta de Linfotoxina , Estructuras Linfoides Terciarias , Animales , Receptor beta de Linfotoxina/metabolismo , Receptor beta de Linfotoxina/genética , Rechazo de Injerto/inmunología , Rechazo de Injerto/patología , Ratones , Estructuras Linfoides Terciarias/inmunología , Estructuras Linfoides Terciarias/patología , Aloinjertos/inmunología , Ratones Endogámicos C57BL , Supervivencia de Injerto/inmunología , Masculino , Modelos Animales de Enfermedad , Ratones Endogámicos BALB C , Humanos , Trasplante HomólogoRESUMEN
The presence of tertiary lymphoid structures (TLSs) associated with distinct treatment efficacy and clinical prognosis has been identified in various cancer types. However, the mechanistic roles and clinical implications of TLSs in genitourinary (GU) cancers remain incompletely explored. Despite their potential role as predictive markers described in numerous studies, it is essential to comprehensively evaluate the characteristics of TLSs, including drivers of formation, structural foundation, cellular compositions, maturation stages, molecular features, and specific functionality to maximize their positive impacts on tumor-specific immunity. The unique contributions of these structures to cancer progression and biology have fueled interest in these structures as mediators of antitumor immunity. Emerging data are trying to explore the effects of therapeutic interventions targeting TLSs. Therefore, a better understanding of the molecular and phenotypic heterogeneity of TLSs may facilitate the development of TLSs-targeting therapeutic strategies to obtain optimal clinical benefits for GU cancers in the setting of immunotherapy. In this review, the authors focus on the phenotypic and functional heterogeneity of TLSs in cancer progression, current therapeutic interventions targeting TLSs and the clinical implications and therapeutic potential of TLSs in GU cancers.
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Estructuras Linfoides Terciarias , Neoplasias Urogenitales , Humanos , Estructuras Linfoides Terciarias/inmunología , Neoplasias Urogenitales/terapia , Neoplasias Urogenitales/inmunología , Neoplasias Urogenitales/patología , Inmunoterapia/métodosRESUMEN
BACKGROUND: Recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC) generally has a poor prognosis for patients with limited treatment options. While incorporating immune checkpoint inhibitors (ICIs) has now become the standard of care, the efficacy is variable, with only a subset of patients responding. The complexity of the tumor microenvironment (TME) and the role of tertiary lymphoid structures (TLS) have emerged as critical determinants for immunotherapeutic response. METHODS: In this study, we analyzed two independently collected R/M HNSCC patient tissue cohorts to better understand the role of TLS in response to ICIs. Utilizing a multi-omics approach, we first performed targeted proteomic profiling using the Nanostring GeoMx Digital Spatial Profiler to quantify immune-related protein expression with spatial resolution. This was further characterized by spatially resolved whole transcriptome profiling of TLSs and germinal centers (GCs). Deeper single-cell resolved proteomic profiling of the TLSs was performed using the Akoya Biosciences Phenocycler Fusion platform. RESULTS: Our proteomic analysis revealed the presence of T lymphocyte markers, including CD3, CD45, and CD8, expressing cells and upregulation of immune checkpoint marker PD-L1 within tumor compartments of patients responsive to ICIs, indicative of 'hot tumor' phenotypes. We also observed the presence of antigen-presenting cells marked by expression of CD40, CD68, CD11c, and CD163 with upregulation of antigen-presentation marker HLA-DR, in patients responding to ICIs. Transcriptome analysis of TLS and GCs uncovered a marked elevation in the expression of genes related to immune modulation, diverse immune cell recruitment, and a potent interferon response within the TLS structure. Notably, the distribution of TLS-tumor distance was found to be significantly different across response groups (H = 9.28, p = 0.026). The proximity of TLSs to tumor cells was found to be a critical indicator of ICI response, implying that patients with TLSs located further from tumor cells have worse outcomes. CONCLUSION: The study underscores the multifaceted role of TLSs in modulating the immunogenic landscape of the TME in R/M HNSCC, likely influencing the efficacy of ICIs. Spatially resolved multi-omics approaches offer valuable insights into potential biomarkers for ICI response and highlight the importance of profiling the TME complexity when developing therapeutic strategies and patient stratification.
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Neoplasias de Cabeza y Cuello , Inmunoterapia , Estructuras Linfoides Terciarias , Microambiente Tumoral , Humanos , Neoplasias de Cabeza y Cuello/inmunología , Neoplasias de Cabeza y Cuello/tratamiento farmacológico , Neoplasias de Cabeza y Cuello/patología , Estructuras Linfoides Terciarias/inmunología , Estructuras Linfoides Terciarias/patología , Microambiente Tumoral/inmunología , Proteómica , Carcinoma de Células Escamosas de Cabeza y Cuello/inmunología , Carcinoma de Células Escamosas de Cabeza y Cuello/tratamiento farmacológico , Carcinoma de Células Escamosas de Cabeza y Cuello/patología , Masculino , Femenino , Resultado del Tratamiento , Persona de Mediana EdadRESUMEN
BACKGROUND: Patients with breast cancer brain metastases (BCBM) experience a rapid decline in their quality of life. Recently, tertiary lymphoid structures (TLSs), analogs of secondary lymphoid organs, have attracted extensive attention. However, the potential clinical implications of TLSs in BCBMs are poorly understood. In this study, we evaluated the density and composition of TLSs in BCBMs and described their prognostic value. METHODS: Clinicopathological data were collected from 98 patients (2015-2021). TLSs were evaluated, and a TLS scoring system was constructed. Differences in progression-free survival (PFS) and overall survival (OS) between groups were calculated using the Kaplan-Meier method. Immunohistochemistry and multiplex immunofluorescence (mIF) were used to assess TLSs heterogeneity. RESULTS: TLSs were identified in 47 patients with BCBM. High TLSs density indicated favorable survival (OS, p=0.003; PFS, p<0.001). TLS was positively associated with OS (p=0.0172) and PFS (p=0.0161) in the human epidermal growth factor receptor type 2-positive subtype, and with prolonged OS (p=0.0482) in the triple-negative breast cancer subtype. The mIF results showed significant differences in the percentages of T follicular helper (Tfh) cells, M2 macrophages, cytotoxic T lymphocytes, and CD8+TIM-3+ T lymphocytes between the groups of TLS scores 0-3 (cytotoxic T lymphocytes, p=0.044; Tfh, p=0.021; M2 macrophages, p=0.033; CD8+TIM-3+ T lymphocytes, p=0.018). Furthermore, novel nomograms incorporating the TLS scores and other clinicopathological predictors demonstrated prominent predictability of the 1-year, 3-year, and 5-year outcomes of BCBMs (area under the curve >0.800). CONCLUSION: Our results highlight the impact of TLSs abundance on the OS and PFS of patients with BCBM. Additionally, we described the immune composition of TLSs and proposed novel nomograms to predict the prognosis of patients with BCBM.
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Neoplasias Encefálicas , Neoplasias de la Mama , Estructuras Linfoides Terciarias , Humanos , Femenino , Estructuras Linfoides Terciarias/inmunología , Estructuras Linfoides Terciarias/patología , Neoplasias de la Mama/patología , Neoplasias de la Mama/inmunología , Neoplasias de la Mama/mortalidad , Neoplasias Encefálicas/secundario , Neoplasias Encefálicas/inmunología , Neoplasias Encefálicas/mortalidad , Persona de Mediana Edad , Pronóstico , Adulto , AncianoRESUMEN
The association of tertiary lymphoid structures (TLSs) with survival and immunotherapy response brought B cells to center stage. In a pan-cancer B cells atlas in Science, Ma et al. show that germinal center reaction generating anti-tumor antibody-secreting cells (ASCs) from B memory cells in mature TLSs co-exist in tumors with extra-follicular reaction generating auto-reactive ASCs from memory B cells in immature TLSs.
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Linfocitos B , Centro Germinal , Neoplasias , Humanos , Linfocitos B/inmunología , Centro Germinal/inmunología , Neoplasias/inmunología , Neoplasias/terapia , Animales , Estructuras Linfoides Terciarias/inmunología , Células B de Memoria/inmunología , Inmunoterapia/métodosRESUMEN
BACKGROUND: Tertiary lymphoid structures (TLSs) are thought to stimulate antitumor immunity and positively impact prognosis and response to immune checkpoint blockade. In gastric cancers (GCs), however, TLSs are predominantly found in GC with poor prognosis and limited treatment response. We, therefore, hypothesize that immune cell composition and function of TLS depends on tumor location and the tumor immune environment. METHODS: Spatial transcriptomics and immunohistochemistry were used to characterize the phenotype of CD45+ immune cells inside and outside of TLS using archival resection specimens from GC primary tumors and peritoneal metastases. RESULTS: We identified significant intrapatient and interpatient diversity of the cellular composition and maturation status of TLS in GC. Tumor location (primary vs metastatic site) accounted for the majority of differences in TLS maturity, as TLS in peritoneal metastases were predominantly immature. This was associated with higher levels of tumor-infiltrating macrophages and Tregs and less plasma cells compared with tumors with mature TLS. Furthermore, mature TLSs were characterized by overexpression of antitumor immune pathways such as B cell-related pathways, MHC class II antigen presentation while immature TLS were associated with protumor pathways, including T cell exhaustion and enhancement of DNA repair pathways in the corresponding cancer. CONCLUSION: The observation that GC-derived peritoneal metastases often contain immature TLS which are associated with immune suppressive regulatory tumor-infiltrating leucocytes, is in keeping with the lack of response to immune checkpoint blockade and the poor prognostic features of peritoneal metastatic GC, which needs to be taken into account when optimizing immunomodulatory strategies for metastatic GC.
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Neoplasias Peritoneales , Neoplasias Gástricas , Estructuras Linfoides Terciarias , Humanos , Neoplasias Gástricas/patología , Neoplasias Gástricas/inmunología , Estructuras Linfoides Terciarias/inmunología , Neoplasias Peritoneales/secundario , Neoplasias Peritoneales/inmunología , Masculino , Femenino , Microambiente TumoralRESUMEN
The capacity of lymphocytes continuously home to lymphoid structures is remarkable for cancer immunosurveillance and immunotherapy. Lymphocyte homing and recirculation within the tumor microenvironment (TME) are now understood to be adaptive processes that are regulated by specialized cytokines and adhesion molecule signaling cascades. Restricted lymphocyte infiltration and recirculation have emerged as key mechanisms contributing to poor responses in cancer immunotherapies like chimeric antigen receptor (CAR)-T cell therapy and immune checkpoint blockades (ICBs). Uncovering the kinetics of lymphocytes in tumor infiltration and circulation is crucial for improving immunotherapies. In this review, we discuss the current insights into the adhesive and migrative molecules involved in lymphocyte homing and transmigration. The potential mechanisms within the TME that restrain lymphocyte infiltration are also summarized. Advanced on these, we outline the determinates for tertiary lymphoid structures (TLSs) formation within tumors, placing high expectations on the prognostic values of TLSs as therapeutic targets in malignancies.
Asunto(s)
Inmunoterapia , Neoplasias , Estructuras Linfoides Terciarias , Microambiente Tumoral , Humanos , Neoplasias/terapia , Neoplasias/inmunología , Estructuras Linfoides Terciarias/inmunología , Microambiente Tumoral/inmunología , Animales , Inmunoterapia/métodos , Linfocitos Infiltrantes de Tumor/inmunología , Linfocitos Infiltrantes de Tumor/metabolismoRESUMEN
INTRODUCTION: Tertiary lymphoid structures (TLS) arise at chronic inflammatory sites where they function as miniature lymph nodes to generate immune responses, which can be beneficial or detrimental, in diseases as diverse as autoimmunity, chronic infections and cancer. A growing number of studies show that a TLS presence in tumors from cancer patients treated with immune checkpoint inhibitors is closely linked with improved clinical outcomes. TLS may foster the generation of specific anti-tumor immune responses and immunological memory that recognizes a patient's own tumor. Due to repeated rounds of chronic inflammation, some tumor-associated TLS may be immunologically inactive, with immune checkpoint inhibitors functioning to revitalize them through pathway activation. AREAS COVERED: This review summarizes work on TLS and how they mediate immune responses in human tumors. We also explore TLS as potential prognostic and predictive biomarkers for immunotherapy. EXPERT OPINION: The presence of TLS in human tumors has been linked with a better clinical prognosis, response to treatment(s) and overall survival. TLS provide a structured microenvironment for the activation, expansion and maturation of immune cells at the tumor site. These activities can enhance the efficacy of immunotherapeutic treatments such as checkpoint inhibitors and cancer vaccines by revitalizing local anti-tumor immunity.
Asunto(s)
Inmunoterapia , Neoplasias , Estructuras Linfoides Terciarias , Microambiente Tumoral , Humanos , Estructuras Linfoides Terciarias/inmunología , Neoplasias/inmunología , Neoplasias/terapia , Inmunoterapia/métodos , Microambiente Tumoral/inmunología , Animales , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Vacunas contra el Cáncer/uso terapéutico , Vacunas contra el Cáncer/inmunologíaRESUMEN
Non-small cell lung cancer (NSCLC) is a common malignancy whose prognosis and treatment outcome are influenced by many factors. Some studies have found that tertiary lymphoid structures (TLSs) in cancer may contribute to prognosis and the prediction of immunotherapy efficacy However, the combined role of TLSs in NSCLC remains unclear. We accessed The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases to obtain mRNA sequencing data and clinical information as the TCGA cohort, and used our own sample of 53 advanced NSCLC as a study cohort. The samples were divided into TLS+ and TLS- groups by pathological tissue sections. Patients of the TLS+ group had a better OS (p = 0.022), PFS (p = 0.042), and DSS (p = 0.004) in the TCGA cohort, and the results were confirmed by the study cohort (PFS, p = 0.012). Furthermore, our result showed that the count and size of TLSs are closely associated with the efficacy of immunotherapy. In addition, the TLS+ group was associated with better immune status and lower tumor mutation load. In the tumor microenvironment (TME), the expression levels of CD4+ T cells and CD8+ T cells of different phenotypes were associated with TLSs. Overall, TLSs are a strong predictor of survival and immunotherapeutic efficacy in advanced NSCLC, and T cell-rich TLSs suggest a more ordered and active immune response site, which aids in the decision-making and application of immunotherapy in the clinic.