Tertiary lymphoid structure score: a promising approach to refine the TNM staging in resected non-small cell lung cancer

Rakaee, Mehrdad; Kilvaer, Thomas K.; Jamaly, Simin; Berg, Thomas; Paulsen, Erna-Elise; Berglund, Marte; Richardsen, Elin; Andersen, Sigve; Al-Saad, Samer; Poehl, Mette; Pezzella, Francesco; Kwiatkowski, David J.; Bremnes, Roy M.; Busund, Lill-Tove; Dønnem, Tom

doi:10.1038/s41416-021-01307-y

Cited by 50 publications

(45 citation statements)

References 44 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Our results suggested that the presence of TLSs was correlated with early TNM stage. Consistent with this, the density of TLSs was also found to be obviously increased in early TNM stage in oral squamous cell carcinoma and NSCLC ( 34 , 35 ). A positive association was found between the presence of TLSs and TIL levels in our study, which might be associated with TLS function.…”

Section: Discussionsupporting

confidence: 78%

The Presence of Tertiary Lymphoid Structures Provides New Insight Into the Clinicopathological Features and Prognosis of Patients With Breast Cancer

et al. 2022

View full text Add to dashboard Cite

BackgroundTertiary lymphoid structures (TLSs) have been proven to be predictive biomarkers of favorable clinical outcomes and response to immunotherapies in several solid malignancies. Nevertheless, the effect of TLSs in patients with breast cancer (BC) remains controversial. The objective of the current study is to investigate the clinicopathological and prognostic significance of TLSs in BC. Given the unique difficulties for detecting and quantifying TLSs, a TLS-associated gene signature based on The Cancer Genome Atlas (TCGA) BC cohort was used to validate and supplement our results.MethodsElectronic platforms (PubMed, Web of Science, EMBASE, the Cochrane Library, CNKI, and Wanfang) were searched systematically to identify relevant studies as of January 11, 2022. We calculated combined odds ratios (ORs) with 95% confidence intervals (CIs) to determine the relationship between clinicopathological parameters and TLSs. The pooled hazard ratios (HRs) and 95% CIs were also calculated to evaluate the prognostic significance of TLSs. The TLS signature based on the TCGA BC cohort was applied to validate and supplement our results.ResultsFifteen studies with 3,898 patients were eligible for enrollment in our study. The combined analysis indicated that the presence of TLSs was related to improved disease-free survival (DFS) (HR = 0.61, 95% CI: 0.41–0.90, p < 0.05) and overall survival (OS) (HR = 1.66, 95% CI: 1.26–2.20, p < 0.001). Additionally, the presence of TLSs was positively correlated with early tumor TNM stage and high tumor-infiltrating lymphocytes. TLS presence was positively related to human epidermal growth factor receptor 2 (HER-2) and Ki-67 but inversely correlated with the status of estrogen and progesterone receptor. Simultaneously, our study found that tumor immune microenvironment was more favorable in the high-TLS signature group than in the low-TLS signature group. Consistently, BC patients in the high-TLS signature group exhibited better survival outcomes compared to those in the low-TLS signature group, suggesting that TLSs might be favorable prognostic biomarkers.ConclusionsTLS presence provides new insight into the clinicopathological features and prognosis of patients with BC, whereas the factors discussed limited the evidence quality of this study. We look forward to consistent methods to define and characterize TLSs, and more high-quality prospective clinical trials designed to validate the value of TLSs alone or in combination with other markers.

show abstract

Section: Discussionsupporting

confidence: 78%

The Presence of Tertiary Lymphoid Structures Provides New Insight Into the Clinicopathological Features and Prognosis of Patients With Breast Cancer

et al. 2022

View full text Add to dashboard Cite

show abstract

“…In mature TLSs of sarcoma patients, the intimate contact between B and T cells was sufficient to induce high expression of the immune checkpoint PD-1 on T cells (Petitprez et al, 2020). Similarly, expression levels of the inhibitory receptors TIGIT and CTLA-4 were elevated in TLS hi non-small cell lung cancer samples compared to the TLS lo ones (Rakaee et al, 2021). Thus, TLSs may represent a rich site of expression of clinically relevant immune checkpoints.…”

Section: Anti-tumor Role Of Tls B Cellsmentioning

confidence: 99%

“…Accumulating evidence indicates that TLSs play a major role in controlling tumor progression ( Teillaud and Dieu-Nosjean, 2017 ; Figure 3 ). Overall, despite the heterogeneity of methods used for quantifying TLSs, studies have consistently found that high densities of intra and peritumoral TLSs are associated with prolonged overall survival and disease-free survival in more than 10 types of malignancies ( Table 1 ), including sarcoma ( Petitprez et al, 2020 ), melanoma ( Cabrita et al, 2020 ), lung ( Dieu-Nosjean et al, 2008 ; Germain et al, 2014 ; Tang et al, 2020 ; Rakaee et al, 2021 ), breast ( Lee H.J. et al, 2016 ; Liu X. et al, 2017 ), colorectal ( Coppola et al, 2011 ; Vayrynen et al, 2014 ) and pancreatic cancers ( Hiraoka et al, 2015 ; Castino et al, 2016 ).…”

Section: Anti-tumor Role Of Tls B Cellsmentioning

confidence: 99%

B Cell Orchestration of Anti-tumor Immune Responses: A Matter of Cell Localization and Communication

Kinker

Vitiello

Ferreira

et al. 2021

Front. Cell Dev. Biol.

View full text Add to dashboard Cite

The immune system plays a crucial role in cancer development either by fostering tumor growth or destroying tumor cells, which has open new avenues for cancer immunotherapy. It was only over the last decade that the role of B cells in controlling anti-tumor immune responses in the tumor milieu has begun to be appreciated. B and plasma cells can exert anti-tumor effects through antibody-dependent cell cytotoxicity (ADCC) and activation of the complement cascade, even though their effector functions extend beyond the classical humoral immunity. In tumor tissues, B cells can be found in lymphoid aggregates, known as tertiary lymphoid structures (TLSs), well-organized non-encapsulated structures composed of immune and stromal cells. These structures reflect a process of lymphoid neogenesis occurring in peripheral tissues upon long-lasting exposure to inflammatory signals. The TLS provides an area of intense B cell antigen presentation that can lead to optimal T cell activation and effector functions, as well as the generation of effector B cells, which can be further differentiated in either antibody-secreting plasma cells or memory B cells. Of clinical interest, the crosstalk between B cells and antigen-experienced and exhausted CD8+ T cells within mature TLS was recently associated with improved response to immune checkpoint blockade (ICB) in melanoma, sarcoma and lung cancer. Otherwise, B cells sparsely distributed in the tumor microenvironment or organized in immature TLSs were found to exert immune-regulatory functions, inhibiting anti-tumor immunity through the secretion of anti-inflammatory cytokines. Such phenotype might arise when B cells interact with malignant cells rather than T and dendritic cells. Differences in the spatial distribution likely underlie discrepancies between the role of B cells inferred from human samples or mouse models. Many fast-growing orthotopic tumors develop a malignant cell-rich bulk with reduced stroma and are devoid of TLSs, which highlights the importance of carefully selecting pre-clinical models. In summary, strategies that promote TLS formation in close proximity to tumor cells are likely to favor immunotherapy responses. Here, the cellular and molecular programs coordinating B cell development, activation and organization within TLSs will be reviewed, focusing on their translational relevance to cancer immunotherapy.

show abstract

“…The association between SLRs and immunotherapy outcomes in lung cancer seems not clear. On the other hand, although total TLS and germinal center-positive (GC+) TLS subset scores were demonstrated to predict survival in resected NSCLC patients ( 29 ), most studies suggested that only TLSs with GC were functional, and B cells in immature TLSs could adopt a regulatory phenotype and inhibit immune reactions ( 30 ). Moreover, we noted the predominant inhibitory Treg cells in post treatment tumor and PD-L1 expression in the lymph node for their crucial roles in immunosuppression.…”

Section: Discussionmentioning

confidence: 99%

Case Report: Sarcoid-Like Reactions and Tertiary Lymphoid Structures Following Dual Checkpoint Inhibition in a Patient with Early-Stage Lung Adenocarcinoma

et al. 2022

View full text Add to dashboard Cite

Immune checkpoint inhibitor-induced sarcoid-like reactions and tertiary lymphoid structures (TLSs) are increasingly recognized but rarely reported in the same patient. We report a patient with lung adenocarcinoma who displayed sarcoid-like reactions in intrathoracic lymph nodes and tertiary lymphoid structures in surgical tumor after neoadjuvant therapy with nivolumab plus ipilimumab. Pathological examination revealed 50% residual tumor cells after treatment, and the CT evaluation of the primary tumor showed a stable disease. The patient experienced a recurrence eight months after surgery. To identify immune correlates of the limited response to immunotherapy, we conducted genomic and transcriptional assays, multiplex immunoassay, and multiplex immunohistochemistry on the pre- and post-immunotherapy tumor, lymph node, and plasma samples. TP53 R181C, KRAS G12C and SMAD4 R361H were identified as driver mutations of the tumor. In addition to abundant infiltrated lymphocytes, immunotherapy induced high levels of inhibitory components in post-treatment tissue samples, especially the FOXP3+ regulatory T cells in tumor and PD-L1 expression in the lymph node. Despite abundant TLSs in the post-treatment tumor, most TLSs were immature. Moreover, increasing levels of circulating checkpoint proteins BTLA, TIM-3, LAG-3, PD-1, PD-L1, and CTLA4 were observed during immunotherapy. Collectively, our observations revealed that high levels of immunosuppressive molecules in tumor, lymph nodes and/or in peripheral blood might indicate poor outcomes after immunotherapy, even in the setting of a patient with concurrent sarcoid-like reactions and tertiary lymphoid structures.

show abstract

Tertiary lymphoid structure score: a promising approach to refine the TNM staging in resected non-small cell lung cancer

Cited by 50 publications

References 44 publications

The Presence of Tertiary Lymphoid Structures Provides New Insight Into the Clinicopathological Features and Prognosis of Patients With Breast Cancer

The Presence of Tertiary Lymphoid Structures Provides New Insight Into the Clinicopathological Features and Prognosis of Patients With Breast Cancer

B Cell Orchestration of Anti-tumor Immune Responses: A Matter of Cell Localization and Communication

Case Report: Sarcoid-Like Reactions and Tertiary Lymphoid Structures Following Dual Checkpoint Inhibition in a Patient with Early-Stage Lung Adenocarcinoma

Contact Info

Product

Resources

About