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STAT3-enhancing germline mutations contribute to tumor-extrinsic immune evasion
Daniel Kogan, … , Christian Faul, Vijay Kumar Ulaganathan
Daniel Kogan, … , Christian Faul, Vijay Kumar Ulaganathan
Published February 13, 2018
Citation Information: J Clin Invest. 2018;128(5):1867-1872. https://doi.org/10.1172/JCI96708.
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Concise Communication Genetics Oncology

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

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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.

Authors

Daniel Kogan, Alexander Grabner, Christopher Yanucil, Christian Faul, Vijay Kumar Ulaganathan

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Figure 1

Expression analysis of FGFR4 in lymphocytes.

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Expression analysis of FGFR4 in lymphocytes.
(A) Representative immunobl...
(A) Representative immunoblot analysis of FGFR4, STAT3, and FOXP3 proteins in purified and pooled lymphocytes (n = 13 adult mice). The histogram shows digital quantification normalized to actin expression bands. The data shown are representative of 3 independent cell isolation and immunoblot experiments. (B) Expression analysis for FGFR4 in CD4+CD25+ and CD4+GITR+ regulatory lymphocytes using fluorochrome-conjugated antibodies in blood, mesenteric lymph nodes, spleen, and thymus isolated from 7-month-old Foxp3-GFP reporter mice. Plots are representative of 5 independent biological replicates.

Copyright © 2023 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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