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

STAT3-enhancing germline mutations contribute to tumor-extrinsic immune evasion.
Author Information (click to view)

Kogan D, Grabner A, Yanucil C, Faul C, Ulaganathan VK,


Kogan D, Grabner A, Yanucil C, Faul C, Ulaganathan VK, (click to view)

Kogan D, Grabner A, Yanucil C, Faul C, Ulaganathan VK,

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The Journal of clinical investigation 2018 02 13() doi 10.1172/JCI96708

Abstract

Immune evasion and the suppression of anti-tumor 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 STAT3 signaling and is associated with poor prognosis and accelerated progression of multiple cancer types. Here, using rs351855 single nucleotide polymorphism (SNP) knock-in transgenic mice and Fgfr4 knockout mice, we reveal the genotype-specific gain of immunological function of suppressing the CD8/CD4+FOXP3+CD25+ve regulatory T cell ratio in vivo. Furthermore, using knock-in 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.

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