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

Abstract

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.

A framework for advancing our understanding of cancer-associated fibroblasts

“…Currently, it is also unclear whether individual CAF populations are preserved across tissues and species. While single-cell sequencing indicates common traits are preserved [49][50][51] , it will become increasingly pressing to define common and specific effects of CAFs. Techniques that provide spatial resolution, such as highly multiplexed antibody-based staining and multiplexed nucleic acid in situ hybridization, will also have a role to play in determining whether CAF subtype is strongly influenced by spatial location within the tumour.…”

Fibroblastic reticular cells predict response to immune checkpoint inhibitors

“…Homing of immune cells into the network requires interaction between chemokines produced by FRCs (CCL19 and CCL21) and their receptor (CCR7) expressed on T cells, B cells and dendritic cells (27, 28; see also Table S1). Accordingly, depleting FRCs causes loss of T cells, B cells and dendritic cells in both SLO and TLS and decreases the magnitude of B and T cell responses to subsequent viral infection (16, 29). Perhaps more importantly, differentiation of fibroblasts into FRCs occurs early during TLS formation, precedes B and T cell infiltration and can still be observed in Rag2-/- mice (29).…”

“…Accordingly, depleting FRCs causes loss of T cells, B cells and dendritic cells in both SLO and TLS and decreases the magnitude of B and T cell responses to subsequent viral infection (16, 29). Perhaps more importantly, differentiation of fibroblasts into FRCs occurs early during TLS formation, precedes B and T cell infiltration and can still be observed in Rag2-/- mice (29). In this context, our finding that a gene expressed in FRCs is associated with ICB response independently of B and T cell infiltration is coherent with the current understanding of TLS neogenesis.…”

“…By conducting a large gene expression study of response to immune checkpoint inhibitors (ICI), we show that pre-treatment expression of B cell genes is associated with ICI response independently of CD8+ T cells. However, we discovered that such association can be completely explained by a single gene ( FDCSP ) expressed outside of the B cell compartment, in fibroblastic reticular cells (FRCs), which form the reticular network that facilitates interactions between B cells, T cells and cognate antigens (4–6) and are required to initiate efficient adaptive immune responses in secondary lymphoid organs (SLO) and tertiary lymphoid structures (TLS) (4, 7). We validated this finding in three independent cohorts of patients treated with ICI in melanoma and renal cell carcinoma.…”

Lymphatic blood filling in CLEC-2-deficient mouse models

“…Podoplanin, the primary ligand for most of the known CLEC-2 functions, is a mucintype protein with a short intracellular tail. It has a broad expression profile including on lymphatic endothelial cells [2], alveolar epithelial type I cells [3,4], stromal cells and fibroblasts [5][6][7], inflammatory leukocytes [4,8,9] and specialized tissue structures such as in kidney podocytes [10] and on choroid plexuses in the brain [11,12]. CLEC-2 (as a consequence of its expression on platelets) and podoplanin have been proposed as novel targets in a wide range of disorders including sepsis, wound repair, infection, and cancer metastasis [4,8,[13][14][15][16][17].…”