Exploring the Role of Tertiary Lymphoid Structures Using a Mouse Model of Bacteria-Infected Lungs

2018 ◽  
pp. 223-239 ◽  
Author(s):  
Jean-Luc Teillaud ◽  
Lucile Regard ◽  
Clémence Martin ◽  
Sophie Sibéril ◽  
Pierre-Régis Burgel
Keyword(s):  
Mouse Model ◽  
Tertiary Lymphoid Structures ◽  
Lymphoid Structures

scholarly journals Insights Into Unveiling a Potential Role of Tertiary Lymphoid Structures in Metastasis

2021 ◽  
Vol 8 ◽  
Author(s):  
Rami Mustapha ◽  
Kenrick Ng ◽  
James Monypenny ◽  
Tony Ng
Keyword(s):  
Antitumor Immunity ◽  
Cancer Metastasis ◽  
Potential Role ◽  
Cancer Invasiveness ◽  
Tertiary Lymphoid Structures ◽  
Lymphoid Structures ◽  
Cancer Dissemination ◽  
Alternative Routes ◽  
Biomechanical Factors

Tertiary lymphoid structures (TLSs) develop in non-lymphatic tissue in chronic inflammation and cancer. TLS can mature to lymph node (LN) like structures with germinal centers and associated vasculature. TLS neogenesis in cancer is highly varied and tissue dependent. The role of TLS in adaptive antitumor immunity is of great interest. However, data also show that TLS can play a role in cancer metastasis. The importance of lymphatics in cancer distant metastasis is clear yet the precise detail of how various immunosurveillance mechanisms interplay within TLS and/or draining LN is still under investigation. As part of the tumor lymphatics, TLS vasculature can provide alternative routes for the establishment of the pre-metastatic niche and cancer dissemination. The nature of the cytokine and chemokine signature at the heart of TLS induction can be key in determining the success of antitumor immunity or in promoting cancer invasiveness. Understanding the biochemical and biomechanical factors underlying TLS formation and the resulting impact on the primary tumor will be key in deciphering cancer metastasis and in the development of the next generation of cancer immunotherapeutics.

scholarly journals Immunofibroblasts are pivotal drivers of tertiary lymphoid structure formation and local pathology

2019 ◽  
Vol 116 (27) ◽  
pp. 13490-13497 ◽  
Author(s):  
Saba Nayar ◽  
Joana Campos ◽  
Charlotte G. Smith ◽  
Valentina Iannizzotto ◽  
David H. Gardner ◽  
...  
Keyword(s):  
Stromal Cells ◽  
Functional Role ◽  
Functional Requirements ◽  
Local Production ◽  
Functional Changes ◽  
Molecular Programming ◽  
Tertiary Lymphoid Structures ◽  
Lymphoid Structures

Resident fibroblasts at sites of infection, chronic inflammation, or cancer undergo phenotypic and functional changes to support leukocyte migration and, in some cases, aggregation into tertiary lymphoid structures (TLS). The molecular programming that shapes these changes and the functional requirements of this population in TLS development are unclear. Here, we demonstrate that external triggers at mucosal sites are able to induce the progressive differentiation of a population of podoplanin (pdpn)-positive stromal cells into a network of immunofibroblasts that are able to support the earliest phases of TLS establishment. This program of events, that precedes lymphocyte infiltration in the tissue, is mediated by paracrine and autocrine signals mainly regulated by IL13. This initial fibroblast network is expanded and stabilized, once lymphocytes are recruited, by the local production of the cytokines IL22 and lymphotoxin. Interfering with this regulated program of events or depleting the immunofibroblasts in vivo results in abrogation of local pathology, demonstrating the functional role of immunofibroblasts in supporting TLS maintenance in the tissue and suggesting novel therapeutic targets in TLS-associated diseases.

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 Tertiary lymphoid structures induced by CXCL13-producing CD4+ T cells increase tumor infiltrating CD8+ T cells and B cells in ovarian cancer

2021 ◽  
Author(s):  
Masayo Ukita ◽  
Junzo Hamanishi ◽  
Hiroyuki Yoshitomi ◽  
Koji Yamanoi ◽  
Shiro Takamatsu ◽  
...  
Keyword(s):  
Gene Expression ◽  
Ovarian Cancer ◽  
T Cells ◽  
B Cells ◽  
Tumor Microenvironment ◽  
Mouse Model ◽  
Tumor Infiltrating Lymphocytes ◽  
Tertiary Lymphoid Structures ◽  
Lymphoid Structures

Background: Tertiary lymphoid structures (TLSs) are transient ectopic lymphoid aggregates whose formation might be caused by chronic inflammation states, such as cancer. The presence of TLS is associated with a favorable prognosis in most solid malignancies. The recognition of the relevance of TLS to cancer has led to a growing interest in TLS as an immunomodulatory target to enhance tumor immunity, although how TLSs are induced in the tumor microenvironment (TME) and how they affect patient survival are not well understood. Methods: TLS distribution in relation to tumor infiltrating lymphocytes (TILs) and related gene expression were investigated in high grade serous ovarian cancer (HGSC) specimens. CXCL13 expression, which is strongly associated with TLS, and its localization in immune cells, were examined. We explored the tumor microenvironment for CXCL13 secretion by adding various inflammatory cytokines in vitro. The induction of TLS by CXCL13 was examined in a mouse model of ovarian cancer. Results: CXCL13 gene expression correlated with TLS formation and the infiltration of T cells and B cells, and was a favorable prognostic factor for HGSC patients. The coexistence of CD8+ T cells and B-cell lineages in the TME was associated with a better prognosis of HGSC and was closely related to the presence of TLSs. CXCL13 expression was predominantly coincident with CD4+ T cells in TLSs and CD8+ T cells in TILs, and shifted from CD4+ T cells to CD21+ follicular dendritic cells as the TLS matured. Although TGF-β was reported to stimulate CXCL13 production, our in vitro results revealed that CXCL13 secretion was promoted in CD4+ T cells under TGF-β + IL-2-restricted conditions and in CD8+ T cells under TGF-β + IL-12-rich conditions. In a mouse model of ovarian cancer, recombinant CXCL13 induced TLSs and enhanced survival by the infiltration of CD8+ T cells. Conclusions: TLS formation was promoted by CXCL13-producing CD4+ T cells and TLSs facilitated the coordinated antitumor responses of cellular and humoral immunity in ovarian cancer.

scholarly journals High Stroma T-Cell Infiltration is Associated with Better Survival in Stage pT1 Bladder Cancer

2020 ◽  
Vol 21 (21) ◽  
pp. 8407
Author(s):  
Sabine Hülsen ◽  
Eleonora Lippolis ◽  
Fulvia Ferrazzi ◽  
Wolfgang Otto ◽  
Luitpold Distel ◽  
...  
Keyword(s):  
Immune Response ◽  
Bladder Cancer ◽  
T Cell ◽  
Immune Cell ◽  
Negative Impact ◽  
Cell Infiltration ◽  
T Cell Infiltration ◽  
Tertiary Lymphoid Structures ◽  
Lymphoid Structures

Stage pT1 bladder cancer (BC) shows highly diverse outcomes. Predictive markers are required to stratify patients for personalized treatment. The present study aimed to validate immune response quantification as a prognostic marker. Patients with pT1 BC (n = 167) treated by transurethral resection of the bladder (TURB) were enrolled. Formaldehyde-fixed paraffin-embedded material was stained for CD3 and CD8. Corresponding T cells were counted in three regions with the highest immune response. Numbers of tertiary lymphoid structures (TLS) and lymphocyte aggregates (LA) were quantified. High CD3+ stroma T-cell infiltration was associated with improved survival (p = 0.045), especially in the G3 subgroup (p = 0.01). Cluster with higher immune response showed less recurrence (p = 0.034) and favorable overall survival (OS) (p = 0.019). In contrast, higher CD3+ and CD8+ tumor T-cell infiltration seemed to have a negative impact on prognosis. TLS and LA were more frequently observed in G3 tumors, indicating an increased anti-tumoral immune response. We proved the role of immune cell infiltration and showed that higher infiltration numbers of CD3+ (not CD8+) lymphocytes in the stroma are associated with favorable outcome. Immune cell quantification could be used as a marker to help stratify patients’ risk and therefore, to optimize patients’ management and follow-up examination as well as possible therapies.

scholarly journals Divergent cancer etiologies drive distinct B cell signatures and tertiary lymphoid structures

2020 ◽  
Author(s):  
Ayana T Ruffin ◽  
Anthony R Cillo ◽  
Tracy Tabib ◽  
Angen Liu ◽  
Sayali Onkar ◽  
...  
Keyword(s):  
B Cells ◽  
Single Cell ◽  
Antitumor Immunity ◽  
Spatial Organization ◽  
Environmental Carcinogens ◽  
Transitional State ◽  
Rnaseq Data ◽  
Tertiary Lymphoid Structures ◽  
Lymphoid Structures

AbstractCurrent immunotherapy paradigms aim to reinvigorate CD8+ T cells, but the contribution of humoral immunity to antitumor immunity remains understudied1,2. Head and neck squamous cell carcinoma (HNSCC) is caused by either human papillomavirus (HPV+) or environmental carcinogens (i.e. tobacco and alcohol; HPV–)3,4. Here, we demonstrate that HPV+ HNSCC patients have transcriptional signatures of germinal center (GC) tumor infiltrating B cells (TIL-Bs) and spatial organization of immune cells consistent with GC-like tertiary lymphoid structures (TLS), both of which correlate with favorable outcomes in HNSCC patients. Further, our single-cell RNAseq data also indicate that GC TIL-Bs are characterized by distinct waves of gene expression consistent with dark zone, light zone and a transitional state of GC B cells. High-dimensional spectral flow cytometry permitted in depth characterization of activated, memory and GC TIL-Bs. Further, single cell RNAseq analysis and subsequent protein validation identified a role for semaphorin 4a (Sema4a) in the differentiation of GC TIL-Bs and indicated that expression of Sema4a was enhanced on GC TIL-Bs and within GC-like TLS in the TME. Thus, in contrast to some reports on the detrimental role of TIL-Bs in human tumors, our findings suggest that TIL-Bs play an instrumental role in antitumor immunity5,6. Novel therapeutics to enhance TIL-B responses in HNSCC should be prioritized as a compliment to current T-cell mediated immunotherapies.

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