Defining High Endothelial Venules and Tertiary Lymphoid Structures in Cancer

IntroductionTo explore the relationship between the tertiary lymphoid structures (TLSs) and tumor-infiltrating lymphocytes (TILs), and their distribution characteristics as well as the prognostic value in gastric cancer (GC).Material and methodsThe TLSs and four subtypes of TILs were assessed by immunohistochemistry (IHC) staining. The presence of MECA-79 positive high endothelial venules (HEVs) identified among the ectopic lymphocyte aggregation area in the GC tissue was defined as a valid TLSs.The number of labeled TILs were observed in 5 fields of the most positive cells in tumor center, invasive edge and within the TLSs, respectively, at a field of vision×40.ResultsThe TLSs distributed significantly higher in the tumor invasive edge than the tumor center (P <0.001). Similarly, the infiltrating density of CD8+T cells and GrB+T cells were highly distributed in the tumor infiltrating edge than the tumor center. While the total number of TILs and the FOXP3+T cells were on the contrary. There was a positive correlation between the density of TLSs and TILs either in the location or the immune phenotype. And a higher frequency of TILs and TLSs often associated with the favorable clinicopathologic parameters. Multivariate analysis revealed that the density of TILs (P= 0.019) and TLSs (P= 0.037) were the independent prognostic predictor for GC patients.ConclusionsThe formation of TLSs predicts an advantageous immune system function and can be considered as a novel biomarker to stratify the overall survival risk of untreated GC patients and as a marker of efficient immunotherapies.

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High Endothelial Venules: A Vascular Perspective on Tertiary Lymphoid Structures in Cancer

Frontiers in Immunology ◽

10.3389/fimmu.2021.736670 ◽

2021 ◽

Vol 12 ◽

Author(s):

Gerlanda Vella ◽

Sophie Guelfi ◽

Gabriele Bergers

Keyword(s):

Immune Response ◽

Endothelial Cells ◽

Cell Aggregates ◽

High Endothelial Venules ◽

Functional Implication ◽

Formation Function ◽

Tertiary Lymphoid Structures ◽

Lymphoid Structures ◽

Secondary Lymphoid Organs ◽

Insight Into

High endothelial venules (HEVs) are specialized postcapillary venules composed of cuboidal blood endothelial cells that express high levels of sulfated sialomucins to bind L-Selectin/CD62L on lymphocytes, thereby facilitating their transmigration from the blood into the lymph nodes (LN) and other secondary lymphoid organs (SLO). HEVs have also been identified in human and murine tumors in predominantly CD3+T cell-enriched areas with fewer CD20+B-cell aggregates that are reminiscent of tertiary lymphoid-like structures (TLS). While HEV/TLS areas in human tumors are predominantly associated with increased survival, tumoral HEVs (TU-HEV) in mice have shown to foster lymphocyte-enriched immune centers and boost an immune response combined with different immunotherapies. Here, we discuss the current insight into TU-HEV formation, function, and regulation in tumors and elaborate on the functional implication, opportunities, and challenges of TU-HEV formation for cancer immunotherapy.

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Faculty Opinions recommendation of Induction of secondary and tertiary lymphoid structures in the skin.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1022294.253695 ◽

2004 ◽

Author(s):

David Chaplin

Keyword(s):

Tertiary Lymphoid Structures ◽

Lymphoid Structures

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Faculty Opinions recommendation of Stromal fibroblasts in tertiary lymphoid structures: A novel target in chronic inflammation.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.727013457.793528869 ◽

2017 ◽

Author(s):

Theresa Lu ◽

William Shipman ◽

Dragos Dasoveanu

Keyword(s):

Chronic Inflammation ◽

Stromal Fibroblasts ◽

Tertiary Lymphoid Structures ◽

Lymphoid Structures ◽

Novel Target

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Mature tertiary lymphoid structures predict immune checkpoint inhibitor efficacy in solid tumors independently of PD-L1 expression

Nature Cancer ◽

10.1038/s43018-021-00232-6 ◽

2021 ◽

Author(s):

Lucile Vanhersecke ◽

Maxime Brunet ◽

Jean-Philippe Guégan ◽

Christophe Rey ◽

Antoine Bougouin ◽

...

Keyword(s):

Solid Tumors ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitor ◽

Checkpoint Inhibitor ◽

Tertiary Lymphoid Structures ◽

Lymphoid Structures

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Agonistic CD40 therapy induces tertiary lymphoid structures but impairs responses to checkpoint blockade in glioma

Nature Communications ◽

10.1038/s41467-021-24347-7 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Luuk van Hooren ◽

Alessandra Vaccaro ◽

Mohanraj Ramachandran ◽

Konstantinos Vazaios ◽

Sylwia Libard ◽

...

Keyword(s):

Checkpoint Inhibitors ◽

Systemic Delivery ◽

Systemic Induction ◽

T Cell Infiltration ◽

Treatment Naïve ◽

Tertiary Lymphoid Structures ◽

Lymphoid Structures ◽

Immunosuppressive Microenvironment ◽

The Brain ◽

Opening Up

AbstractGliomas are brain tumors characterized by an immunosuppressive microenvironment. Immunostimulatory agonistic CD40 antibodies (αCD40) are in clinical development for solid tumors, but are yet to be evaluated for glioma. Here, we demonstrate that systemic delivery of αCD40 in preclinical glioma models induces the formation of tertiary lymphoid structures (TLS) in proximity of meningeal tissue. In treatment-naïve glioma patients, the presence of TLS correlates with increased T cell infiltration. However, systemic delivery of αCD40 induces hypofunctional T cells and impairs the response to immune checkpoint inhibitors in pre-clinical glioma models. This is associated with a systemic induction of suppressive CD11b+ B cells post-αCD40 treatment, which accumulate in the tumor microenvironment. Our work unveils the pleiotropic effects of αCD40 therapy in glioma and reveals that immunotherapies can modulate TLS formation in the brain, opening up for future opportunities to regulate the immune response.

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