Dataset Information

Interferon responsive high endothelial venules drive tumor tertiary lymphoid structure formation and predict response to anti-PD-1 immunotherapy in nasopharyngeal carcinoma

ABSTRACT: The outcome of immune checkpoint blockade (ICB) therapy largely hinges on the antitumor immune response of tertiary lymphoid structures (TLSs), but the driver factors behind tumor TLS formation remain poorly understood. Through integrated analysis of spatial and pan-cancer single-cell transcriptomics, we reveal the characteristics of TLSs in nasopharyngeal carcinoma (NPC) and identify a subset of interferon responsive high endothelial venules (IFN-HEVs) that is responsible for the emergence of tumor-specific chemokines, especially CXCL9. Functionally, IFN-HEVs facilitate the recruitment of CD4+ T cells into TLSs via the CXCL9-CXCR3 axis. IFN-HEV-related phenotypes are strongly correlated with positive prognostic outcomes and better responses to ICB therapy. Leveraging these phenotypes, we develop a pretreatment CXCL9-TLS Response-predictive scoring system (CTRscore) to forecast the efficacy of ICB therapy and validate its predictive efficiency in three independent NPC cohorts. Our study provides biological and functional insights into the IFN-HEVs in tumor TLSs, highlighting their potential role in the development of biomarkers and predictors for the success of ICB therapy.

ORGANISM(S): Homo sapiens

PROVIDER: GSE289272 | GEO | 2025/05/02

REPOSITORIES: GEO

ACCESS DATA

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

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.

Dataset Information

Interferon responsive high endothelial venules drive tumor tertiary lymphoid structure formation and predict response to anti-PD-1 immunotherapy in nasopharyngeal carcinoma

Dataset's files

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets