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Spatial deconvolution of tertiary lymphoid structure in human IPF lungs revealed novel CCL19-expressing mural cells

ABSTRACT: Tertiary lymphoid structures (TLS) are commonly observed in human idiopathic pulmonary fibrosis (IPF) lungs. The specific immune and non-immune cells in the TLS of IPF patients, and the factors that drive TLS formation, remain largely unknown. Here we spatially deconvoluted immune and non-immune cells in the TLS of human IPF lungs, and examined the signals underlying TSL development in IPF patients. We identified a novel subset of CCL19hi-IPF-associated-mural cells (CCL19hiIAMC) that enveloped the vessels inside the TLS. CCL19hiIAMCs were the major source of CCL19 inside the TLS of IPF lungs, attracting T/B lymphocytes and unique CCR7+DCs to drive TLS formation. CCL19hiIAMCs also provided other pro-TLS and proinflammatory molecules to promote lymphocyte maturation and tissue inflammation. Our data also reveal that various IPF-associated fibroblasts surrounded the TLS, promoting TLS development and plasma cells dissemination via CXCL12/CXCR4 signaling. CCR7 and CXCR4 signaling attracted lymphocytes and DCs that upregulated pro-TLS genes in the IPF microenvironment to enhance TLS formation. Together, these findings have deconvoluted the cell subsets and their transcriptomes in the TLS of IPF lungs and suggest that novel CCL19hiIAMCs may drive TLS formation in collaboration with various immune cells and fibroblasts.

ORGANISM(S): Homo sapiens

PROVIDER: GSE248082 | GEO | 2024/11/22

REPOSITORIES: GEO

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Project description:Background and aims: Tertiary lymphoid structures (TLSs) are formed in many cancer types and have been correlated with better prognosis and response to immunotherapy. In liver cancer, TLSs have been reported to be pro-tumorigenic as they harbor tumor progenitor cells and nurture their growth. The processes involved in TLS development and the acquisition of a pro- or anti-tumorigenic phenotype in cancer are largely unknown. RORc expressing immune cells have been previously implicated in TLS formation, however, their role in TLS development in the context of inflammation-associated liver cancer remains unexplored. Methods: IKKβ(EE)Hep mice, exhibiting chronic liver inflammation and TLS formation followed by liver cancer, were crossed with RORc knockout mice to explore the effect of RORc on TLS and tumor formation. Transcriptional, proteomic and immunohistochemical techniques were used to analyze TLS phenotypes. CD4, CD8 and B cell depletions were used to analyze their contribution to liver TLS and tumor formation. Results: RORc expressing cells were detected within TLSs of both human patients and mice which develop intrahepatic cholangiocarcinoma. In mice, RORc expressing cells negatively regulate TLS formation, since in their absence TLSs form in excess. CD4 cells are essential for liver TLS formation whereas B cells are required for TLS formation specifically in the absence of RORc expressing cells. Importantly, in chronically inflamed livers lacking RORc expressing cells, TLSs become anti-tumorigenic, resulting in reduced tumor load. Comparing liver pro- and anti-tumorigenic TLSs, revealed enrichment of exhausted CD8 cells that retained effector functions, as well as germinal center B cells and plasma cells in anti-tumorigenic TLSs. Cell depletion experiments revealed a role mainly for B cells in limiting tumor development, possibly via tumor-directed antibodies. Conclusions: RORc expressing cells negatively regulate B cell responses, and facilitate the pro-tumorigenic functions of hepatic TLSs.