STAT3-enhancing germline mutations contribute to tumor-extrinsic immune evasion

Kogan, Daniel; Grabner, Alexander; Yanucil, Christopher; Faul, Christian und Ulaganathan, Vijay Kumar (2018): STAT3-enhancing germline mutations contribute to tumor-extrinsic immune evasion. In: Journal of Clinical Investigation, Bd. 128, Nr. 5: S. 1867-1872

Abstract

Immune evasion and the suppression of antitumor responses during cancer progression are considered hallmarks of cancer and are typically attributed to tumor-derived factors. Although the molecular basis for the crosstalk between tumor and immune cells is an area of active investigation, whether host-specific germline variants can dictate immunosuppressive mechanisms has remained a challenge to address. A commonly occurring germline mutation (c.1162G>A/rs351855 G/A) in the FGFR4 (CD334) gene enhances signal transducer and activator of transcription 3 (STAT3) signaling and is associated with poor prognosis and accelerated progression of multiple cancer types. Here, using rs351855 SNP-knockin transgenic mice and Fgfr4-knockout mice, we reveal the genotype-specific gain of immunological function of suppressing the CD8/CD4(+)FOXP3(+)CD25(+) regulatory T cell ratio in vivo. Furthermore, using knockin transgenic mouse models for lung and breast cancers, we establish the host-specific, tumor-extrinsic functions of STAT3-enhancing germline variants in impeding the tumor infiltration of CD8 T cells. Thus, STAT3-enhancing germline receptor variants contribute to immune evasion through their pleiotropic functions in immune cells.

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Mathematik, Informatik und Statistik
• Themengebiete: 500 Naturwissenschaften und Mathematik > 510 Mathematik
• ISSN: 0021-9738
• Sprache: Englisch