Sensory nerves in melanoma impede the formation of tertiary lymphoid structures and anti-tumor immune responses

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.

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PD-1+CXCR5−CD4+ Th-CXCL13 cell subset drives B cells into tertiary lymphoid structures of nasopharyngeal carcinoma

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2020-002101 ◽

2021 ◽

Vol 9 (7) ◽

pp. e002101

Author(s):

Jiang-Ping Li ◽

Chang-You Wu ◽

Ming-Yuan Chen ◽

Shang-Xin Liu ◽

Shu-Mei Yan ◽

...

Keyword(s):

B Cells ◽

Nasopharyngeal Carcinoma ◽

Immune Responses ◽

Transforming Growth Factor Beta ◽

Tumor Antigens ◽

Transforming Growth Factor ◽

Cell Subset ◽

Histological Evaluation ◽

Tertiary Lymphoid Structures ◽

Lymphoid Structures

BackgroundA major current challenge is to exploit tertiary lymphoid structures (TLSs) to promote the lymphocyte infiltration, activation and differentiation by tumor antigens to increase antitumor immune responses. The mechanisms that underlie the role of TLS formation in the adaptive immune responses against nasopharyngeal carcinoma (NPC) remain largely unknown.MethodsCell populations and the corresponding markers were identified by single-cell RNA sequencing and fluorescence-activated cell sorting analysis. In vitro differentiation experiments were used to simulate the generation, regulation and function of the Th-CXCL13 cell subset in the tumor microenvironment of NPC. These were followed by histological evaluation of the colocalization of tumor-associated B cells (TABs) and Th-CXCL13 cells within TLSs, and statistical analysis of the relationship between the cells in TLSs and overall survival.ResultsA PD-1+CXCR5−CD4+ Th-CXCL13 cell subset was identified in NPC. This subset was a major source of CXCL13, representing the majority of the CD4+ T cells at levels comparable with Th1 and Tfh cells present in the TLSs. Monocytes activated by toll-like receptor 4 agonists served as the antigen-presenting cells that most efficiently triggered the expansion of Th-CXCL13 cells. Transforming growth factor beta 1 (TGF-β1) stimulation and activation of Sox4 were critical for the induction and polarization of Th-CXCL13 cells in this process. The potential functional contributions of TABs recruited by Th-CXCL13 cells which induced plasma cell differentiation and immunoglobulin production via interleukin-21 and CD84 interactions in the TLSs demonstrated improved survival.ConclusionsInduction of Th-CXCL13 cells links innate inflammation to immune privilege in tumor-associated TLSs and might predict better survival.

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TGF-β induced CXCL13 in CD8+ T cells is associated with tertiary lymphoid structures in cancer

10.1101/303834 ◽

2018 ◽

Cited By ~ 1

Author(s):

HH Workel ◽

JM Lubbers ◽

R Arnold ◽

T Prins ◽

P van der Vlies ◽

...

Keyword(s):

T Cells ◽

Immune Responses ◽

Cd8 T Cells ◽

Transforming Growth Factor Beta ◽

Transforming Growth Factor ◽

Human Tumors ◽

Unexpected Finding ◽

Follicular Helper ◽

Tertiary Lymphoid Structures ◽

Lymphoid Structures

AbstractCoordinated immune responses against human tumors are frequently characterized by tertiary lymphoid structures (TLS) which predict improved prognosis. The development of TLS is dependent on the chemokine CXCL13, reported to be secreted by dendritic cells and follicular helper T cells only. We report the unexpected finding that CXCL13 is also secreted by activated CD8+ T cells following stimulation by transforming growth factor beta (TGF-β). Using single cell RNA sequencing we found that expression ofCXCL13in CD8+ T cells was restricted to the intraepithelial CD103+ population. Accordingly, CD8+ T cells activated in the presence of TGF-β simultaneously upregulated CD103 and secreted CXCL13.CXCL13expression was strongly correlated with neo-antigen burden and cytolytic gene signatures in bulk tumors. In line with this, TLS were abundant in neo-antigen-high, CD103+ T cell-enriched tumors. TGF-β thus appears to play a role in coordinating immune responses against human tumors through CD8-dependent CXCL13-associated formation of TLS.

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Abstract P5-04-12: Functional CXCR5+CD4+follicular helper T cells in breast cancer associated tertiary lymphoid structures signal active immune responses at the tumor site

10.1158/1538-7445.sabcs19-p5-04-12 ◽

2020 ◽

Author(s):

Karen Willard-Gallo ◽

Gregory Noel ◽

Mireille Langouo Fontsa ◽

Soizic Garaud ◽

Alexandre de Wind ◽

...

Keyword(s):

Breast Cancer ◽

T Cells ◽

Immune Responses ◽

Helper T Cells ◽

Tumor Site ◽

Follicular Helper T Cells ◽

Follicular Helper ◽

Tertiary Lymphoid Structures ◽

Lymphoid Structures

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Dendritic cells are crucial for maintenance of tertiary lymphoid structures in the lung of influenza virus–infected mice

Journal of Experimental Medicine ◽

10.1084/jem.20090410 ◽

2009 ◽

Vol 206 (11) ◽

pp. 2339-2349 ◽

Cited By ~ 212

Author(s):

Corine H. GeurtsvanKessel ◽

Monique A.M. Willart ◽

Ingrid M. Bergen ◽

Leonie S. van Rijt ◽

Femke Muskens ◽

...

Keyword(s):

T Cells ◽

Dendritic Cells ◽

Influenza Virus ◽

Immune Responses ◽

Plasma Cells ◽

Influenza Virus Infection ◽

Infectious Agents ◽

Virus Clearance ◽

Tertiary Lymphoid Structures ◽

Lymphoid Structures

Tertiary lymphoid organs (TLOs) are organized aggregates of B and T cells formed in postembryonic life in response to chronic immune responses to infectious agents or self-antigens. Although CD11c+ dendritic cells (DCs) are consistently found in regions of TLO, their contribution to TLO organization has not been studied in detail. We found that CD11chi DCs are essential for the maintenance of inducible bronchus-associated lymphoid tissue (iBALT), a form of TLO induced in the lungs after influenza virus infection. Elimination of DCs after the virus had been cleared from the lung resulted in iBALT disintegration and reduction in germinal center (GC) reactions, which led to significantly reduced numbers of class-switched plasma cells in the lung and bone marrow and reduction in protective antiviral serum immunoglobulins. Mechanistically, DCs isolated from the lungs of mice with iBALT no longer presented viral antigens to T cells but were a source of lymphotoxin (LT) β and homeostatic chemokines (CXCL-12 and -13 and CCL-19 and -21) known to contribute to TLO organization. Like depletion of DCs, blockade of LTβ receptor signaling after virus clearance led to disintegration of iBALT and GC reactions. Together, our data reveal a previously unappreciated function of lung DCs in iBALT homeostasis and humoral immunity to influenza virus.

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