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

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.

scholarly journals Mechanisms of Environment-Induced Autoimmunity

2021 ◽  
Vol 61 (1) ◽  
pp. 135-157 ◽  
Author(s):  
K. Michael Pollard ◽  
David M. Cauvi ◽  
Jessica M. Mayeux ◽  
Christopher B. Toomey ◽  
Amy K. Peiss ◽  
...  
Keyword(s):  
Environmental Exposures ◽  
Particulate Material ◽  
Diagnostic Specificity ◽  
Histocompatibility Complex ◽  
Persistent Inflammation ◽  
Gene Environment ◽  
Tertiary Lymphoid Structures ◽  
Lymphoid Structures ◽  
Insight Into

Although numerous environmental exposures have been suggested as triggers for preclinical autoimmunity, only a few have been confidently linked to autoimmune diseases. For disease-associated exposures, the lung is a common site where chronic exposure results in cellular toxicity, tissue damage, inflammation, and fibrosis. These features are exacerbated by exposures to particulate material, which hampers clearance and degradation, thus facilitating persistent inflammation. Coincident with exposure and resulting pathological processes is the posttranslational modification of self-antigens, which, in concert with the formation of tertiary lymphoid structures containing abundant B cells, is thought to promote the generation of autoantibodies that in some instances demonstrate major histocompatibility complex restriction. Under appropriate gene-environment interactions, these responses can have diagnostic specificity. Greater insight into the molecular and cellular requirements governing this process, especially those that distinguish preclinical autoimmunity from clinical autoimmunedisease, may facilitate determination of the significance of environmental exposures in human autoimmune disease.

scholarly journals The relationship of the tertiary lymphoid structures with the tumor-infiltrating lymphocytes and its prognostic value in gastric cancer

2021 ◽  
Author(s):  
Nana Zhang ◽  
Guanjun Zhang ◽  
Depu Wang ◽  
Hao Liu ◽  
Yuchi Zhang ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
T Cells ◽  
Prognostic Value ◽  
Tumor Infiltrating Lymphocytes ◽  
High Endothelial Venules ◽  
Tumor Center ◽  
Tertiary Lymphoid Structures ◽  
Lymphoid Structures ◽  
Infiltrating Lymphocytes ◽  
The Relationship

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.

Role of intratumoral tertiary lymphoid structures as key modulators in the antitumor immune response in pancreatic cancer

Pancreatology ◽  
2020 ◽  
Vol 20 ◽  
pp. S125
Author(s):  
C. Mota Reyes ◽  
R. Istvanffy ◽  
O. Safak ◽  
B. Konukiewitz ◽  
A. Muckenhuber ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Immune Response ◽  
Antitumor Immune Response ◽  
Tertiary Lymphoid Structures ◽  
Lymphoid Structures

scholarly journals P03.03 Organization, function and gene expression of tertiary lymphoid structures in PDAC resembles lymphoid follicles in secondary lymphoid organs

2020 ◽  
Vol 8 (Suppl 2) ◽  
pp. A23.1-A23
Author(s):  
M Thelen ◽  
MA García-Márquez ◽  
T Nestler ◽  
S Wagener-Ryczek ◽  
J Lehmann ◽  
...  
Keyword(s):  
Gene Expression ◽  
Immune Responses ◽  
Expression Patterns ◽  
Lymphoid Organs ◽  
Immunofluorescence Staining ◽  
Ductal Adenocarcinoma ◽  
Lymphoid Follicles ◽  
Tertiary Lymphoid Structures ◽  
Lymphoid Structures ◽  
Secondary Lymphoid Organs

BackgroundSecondary lymphoid organs (SLO) are involved in induction and enhancement of anti-tumor immune responses on different tumor entities. Recent evidence suggests that anti-tumor immune responses may also be induced or enhanced in the tumor microenvironment in so called tertiary lymphoid structures (TLS). It is assumed that TLS represent a hotspot for T cell priming, B cell activation, and differentiation, leading to cellular and humoral anti-tumor immune response.MethodsFFPE-slides of 120 primary pancreatic ductal adenocarcinoma (PDAC) patients were immunohistochemically (IHC) stained for CD20, CD3, CD8 and HLA-ABC to analyze spatial distribution of tumor-infiltrating lymphocytes. 5-color immunofluorescence staining was performed to further investigate structural components of TLS in comparison to lymphoid follicles in SLOs. Microscope-based laser microdissection and Nanostring-base RNA expression analysis were used to compare gene expression in PDAC, TLS, SLOs and normal pancreatic tissue.ResultsTLS were frequently detected in PDAC and were mainly localized along the invasive tumor margin. In less than 10% of the cases TLS were infiltrating the tumors. Interestingly, 20% of the patients had no TLS. Results of TLS will be correlated with clinical parameters, Immunoscore and immune escape mechanisms. 5-color Immunofluorescence staining revealed similar organization and function of TLS and SLO. Finally, gene expression analyzed by Nanostring revealed largely overlapping expression patterns in TLS and SLO.ConclusionsThe results clearly demonstrate close similarities between SLO and TLS in terms of composition, distribution and gene expression Patterns.Disclosure InformationM. Thelen: None. M.A. García-Márquez: None. T. Nestler: None. S. Wagener-Ryczek: None. J. Lehmann: None. E. Staib: None. F. Popp: None. F. Gebauer: None. P. Lohneis: None. M. Odenthal: None. S. Merkelbach-Bruse: None. C. Bruns: None. K. Wennhold: None. M. von Bergwelt-Baildon: None. H.A. Schlößer: None.

scholarly journals Developing ovine mammary terminal duct lobular units have a dynamic mucosal and stromal immune microenvironment

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Dorottya Nagy ◽  
Clare M. C. Gillis ◽  
Katie Davies ◽  
Abigail L. Fowden ◽  
Paul Rees ◽  
...  
Keyword(s):  
Mammary Gland ◽  
Immune Cell ◽  
Leading Edge ◽  
Breast Development ◽  
Cell Aggregates ◽  
Human Breast ◽  
Immune Microenvironment ◽  
Ki67 Expression ◽  
Tertiary Lymphoid Structures ◽  
Lymphoid Structures

AbstractThe human breast and ovine mammary gland undergo striking levels of postnatal development, leading to formation of terminal duct lobular units (TDLUs). Here we interrogate aspects of sheep TDLU growth as a model of breast development and to increase understanding of ovine mammogenesis. The distributions of epithelial nuclear Ki67 positivity differ significantly between younger and older lambs. Ki67 expression is polarised to the leading edge of the developing TDLUs. Intraepithelial ductal macrophages exhibit periodicity and considerably increased density in lambs approaching puberty. Stromal macrophages are more abundant centrally than peripherally. Intraepithelial T lymphocytes are more numerous in older lambs. Stromal hotspots of Ki67 expression colocalize with immune cell aggregates that exhibit distinct organisation consistent with tertiary lymphoid structures. The lamb mammary gland thus exhibits a dynamic mucosal and stromal immune microenvironment and constitutes a valuable model system that provides new insights into postnatal breast development.

scholarly journals Tertiary lymphoid structures related B-cell IgE isotype switching and secondary lymphoid organs linked IgE production in mouse allergy model

2020 ◽  
Author(s):  
Dmitrii Borisovich Chudakov ◽  
Dmitrii Yur'yevich Ryasantsev ◽  
Daria Sergeevna Tsaregorotseva ◽  
Olga Dmitrievna Kotsareva ◽  
Gulnar Vaisovna Fattakhova
Keyword(s):  
Lymph Nodes ◽  
B Cell ◽  
Genotoxic Stress ◽  
Specific Ige ◽  
Lymphoid Organs ◽  
Antibody Isotype ◽  
Isotype Switching ◽  
Tertiary Lymphoid Structures ◽  
Lymphoid Structures ◽  
Secondary Lymphoid Organs

Abstract Background: Numerous data obtained by different research laboratories around the world indicate that specific IgE production is triggered independently of specific IgG or IgA production and so did not linked to fully matured germinal centers of secondary lymphoid organs. The aim of this study is to clarify whether specific IgE production is triggered by low antigen doses administrated in tertiary lymphoid structure enriched tissues.Methods: OVA in different doses (100 ng or 10 µg) was administrated three times a week for 4–5 weeks intraperitoneally and subcutaneously to female BALB/c mice in the withers region enriched in fat-associated lymphoid clusters and in foot pad region not containing them.Results: OVA-specific IgE was predominantly induced by low but not by high antigen doses and only after immunization in withers. IgE isotype switching was triggered exclusively in withers adipose tissue but not in regional lymph nodes though mature IgE expressing cells were observed both in tissue and lymph nodes. Anti-proliferative genotoxic stress inducing drugs shifted the balance from IgG1 towards IgE production.Conclusion. Tertiary lymphoid structures possess unique environment where B-cell antibody isotype switching to IgE predominantly occurs. These phenomena are explained by hampered proliferation of B-cells in these structures.

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