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Mutant p53 elicits context-dependent pro-tumorigenic phenotypes (microarray)

ABSTRACT: Mutant p53 elicits context-dependent pro-tumorigenic phenotypes (microarray)

PROVIDER: PRJNA660982 | ENA |

REPOSITORIES: ENA

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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.

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Mutant p53 elicits context-dependent pro-tumorigenic phenotypes (microarray)

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