Fibroblasts as a source of self-antigens for central immune tolerance

Nitta, Takeshi; Tsutsumi, Masanori; Nitta, Sachiko; Muro, Ryunosuke; Suzuki, Emma C.; Nakano, Kenta; Tomofuji, Yoshihiko; Sawa, Shinichiro; Okamura, Tadashi; Penninger, Josef; Takayanagi, Hiroshi

doi:10.1038/s41590-020-0756-8

Cited by 68 publications

(164 citation statements)

References 56 publications

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“…The holistic interrogation of tumorassociated elements with technologies such as single cell sequencing further enhanced the cellular resolution of CAFs and the tumor microenvironment 46,48,49,72,74,[81][82][83][84][85][86][87][88] . Studies in nontumor sites have also started to highlight the global heterogeneity of these cells in various organs and across different diseases, indicating that the existence of functionally diverse fibroblast subsets is not restricted to tumor tissues [89][90][91][92][93][94][95] .…”

Section: Discussionmentioning

confidence: 99%

TGFβ-blockade uncovers stromal plasticity in tumors by revealing the existence of a subset of interferon-licensed fibroblasts

Grauel¹,

Nguyen²,

et al. 2020

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Despite the increasing interest in targeting stromal elements of the tumor microenvironment, we still face tremendous challenges in developing adequate therapeutics to modify the tumor stromal landscape. A major obstacle to this is our poor understanding of the phenotypic and functional heterogeneity of stromal cells in tumors. Herein, we perform an unbiased interrogation of tumor mesenchymal cells, delineating the co-existence of distinct subsets of cancer-associated fibroblasts (CAFs) in the microenvironment of murine carcinomas, each endowed with unique phenotypic features and functions. Furthermore, our study shows that neutralization of TGFβ in vivo leads to remodeling of CAF dynamics, greatly reducing the frequency and activity of the myofibroblast subset, while promoting the formation of a fibroblast population characterized by strong response to interferon and heightened immunomodulatory properties. These changes correlate with the development of productive anti-tumor immunity and greater efficacy of PD1 immunotherapy. Along with providing the scientific rationale for the evaluation of TGFβ and PD1 co-blockade in the clinical setting, this study also supports the concept of plasticity of the stromal cell landscape in tumors, laying the foundation for future investigations aimed at defining pathways and molecules to program CAF composition for cancer therapy.

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Section: Discussionmentioning

confidence: 99%

TGFβ-blockade uncovers stromal plasticity in tumors by revealing the existence of a subset of interferon-licensed fibroblasts

Grauel¹,

Nguyen²,

et al. 2020

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“…Recently, we developed an enzymatic digestion method that allows the fractionation of thymic cells based on their intrathymic localization ( 79 ). Thymic fibroblasts were enriched in the fractions that correspond to the capsule and medulla, enabling the isolation of capFbs and mFbs.…”

Section: Capsular Fibroblastsmentioning

confidence: 99%

“…Thymic fibroblasts were enriched in the fractions that correspond to the capsule and medulla, enabling the isolation of capFbs and mFbs. Among the differentially expressed genes, we identified Dpp4 , a gene encoding the cell-surface protease dipeptidyl peptidase-4 (also called CD26), which is specifically expressed in capFbs and, consequently, established a means to separate capFbs (DPP4 + gp38 + ) and mFbs (DPP4 − gp38 + ) by flow cytometry and by histological analyses ( 79 ).…”

Section: Capsular Fibroblastsmentioning

confidence: 99%

“…mFbs resemble fibroblastic reticular cells (FRCs) that form conduit-like network in secondary lymphoid organs, and they have also been known as thymic FRCs ( 71 , 82 ). Transcriptome analyses on mFbs and LN FRCs revealed possible functional differences between these two morphologically similar cell types ( 79 , 83 ). LN FRCs are subdivided into several types based on their expression of functional genes, including chemokines and cytokines: T-cell zone reticular cell (TRC) expressing Ccl19 , Ccl21a , and Il7 ; follicular dendritic cell (FDC) expressing Cxcl13 ; marginal reticular cell (MRC) expressing Tnfsf11 (RANKL); Cxcl12-expressing reticular cell (CRC); and medullary reticular cell (medRC) expressing Cxcl12 , Il6 , Tnfsf13 , and Tnfsf13b .…”

Section: Medullary Fibroblastsmentioning

confidence: 99%

“…We demonstrated that the LTβR expressed in mFbs is pivotal for the induction of T cell tolerance. LTβR-dependent, mFb-associated genes include certain TRAs, and mice specifically lacking LTβR in thymic fibroblasts exhibited a marked production of autoantibodies against those TRAs ( 79 ). The fibroblast-specific LTβR-deficient mice displayed signs of autoimmunity against peripheral tissues in a manner that was similar to systemic LTβR-deficient mice.…”

Section: Medullary Fibroblastsmentioning

confidence: 99%

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Non-Epithelial Thymic Stromal Cells: Unsung Heroes in Thymus Organogenesis and T Cell Development

Nitta

Takayanagi

2021

Front. Immunol.

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The stromal microenvironment in the thymus is essential for generating a functional T cell repertoire. Thymic epithelial cells (TECs) are numerically and phenotypically one of the most prominent stromal cell types in the thymus, and have been recognized as one of most unusual cell types in the body by virtue of their unique functions in the course of the positive and negative selection of developing T cells. In addition to TECs, there are other stromal cell types of mesenchymal origin, such as fibroblasts and endothelial cells. These mesenchymal stromal cells are not only components of the parenchymal and vascular architecture, but also have a pivotal role in controlling TEC development, although their functions have been less extensively explored than TECs. Here, we review both the historical studies on and recent advances in our understanding of the contribution of such non-TEC stromal cells to thymic organogenesis and T cell development. In particular, we highlight the recently discovered functional effect of thymic fibroblasts on T cell repertoire selection.

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Inducing Ectopic T Cell Clusters Using Stromal Vascular Fraction Spheroid‐Based Immunotherapy to Enhance Anti‐Tumor Immunity

et al. 2022

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Tertiary lymphoid structures (TLSs) provide specialized niches for immune cells, resulting in improved prognoses for patients undergoing cancer immunotherapy. Shaping TLS‐like niches may improve anti‐cancer immunity and overcome the current limitations of immune cell‐based immunotherapy. Here, it is shown that stromal vascular fraction (SVF) from adipose tissues can enhance dendritic cell (DC)‐mediated T cell immunity by inducing ectopic T lymphocyte clusters. SVF cells expanded ex vivo have phenotypes and functions similar to those of fibroblastic reticular cells in a secondary lymphoid organ, and their properties can be modulated using three‐dimensional spheroid culture and coculture with DCs spiked with antigen‐loaded iron oxide–zinc oxide core‐shell nanoparticles. Thereby, the combination of SVF spheroids and mature DCs significantly augments T cell recruitment and retention at the injection site. This strategy elicits enhanced antigen‐specific immune response and anti‐tumoral immunity in mice, illustrating the potential for a novel immunotherapeutic design using SVF as a structural scaffold for TLS.

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Fibroblasts as a source of self-antigens for central immune tolerance

Cited by 68 publications

References 56 publications

TGFβ-blockade uncovers stromal plasticity in tumors by revealing the existence of a subset of interferon-licensed fibroblasts

TGFβ-blockade uncovers stromal plasticity in tumors by revealing the existence of a subset of interferon-licensed fibroblasts

Non-Epithelial Thymic Stromal Cells: Unsung Heroes in Thymus Organogenesis and T Cell Development

Inducing Ectopic T Cell Clusters Using Stromal Vascular Fraction Spheroid‐Based Immunotherapy to Enhance Anti‐Tumor Immunity

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