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 May 1, 2018; First 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

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 3

Genotype-specific suppression of the CD8/Treg ratio ex vivo.

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Genotype-specific suppression of the CD8/Treg ratio ex vivo. (A) Dye dil...
(A) Dye dilution assay assessing the proliferative capacities of eFluor670- and CFSE-loaded CD4+CD25+ Tregs and CD8 T cells, respectively, 72 hours after CD3/CD28 stimulation of cells isolated from spleens of Fgfr4rs351855–A/A and Fgfr4rs351855–G/G mice. (B) In vitro suppression assays with CD4+CD25+ Tregs from Fgfr4rs351855–G/G and Fgfr4rs351855–A/A mice together with CD8 T cells from Fgfr4rs351855–G/G and Fgfr4rs351855–A/A mice, respectively. Tregs and CD8 T cells were mixed at different ratios and stimulated using mouse T-activator CD3/CD28 Dynabeads. Three days after stimulation, the percentage of suppression was calculated as described in Methods. Data are representative of 3 independent experiments. For each experiment, cells were isolated from a group of 5 mice of either genotype, and each mixed ratio was cocultivated in replicates of 5 wells (mean ± SEM, NS = not significant, *P < 0.05, **P < 0.01, ***P < 0.001). Statistical comparisons of groups were performed by 2-way ANOVA using Sidak’s multiple comparisons test. (C) Graphic summary illustrating the SNP-specific gain of immunological function by the minor allele (NC_000005.10:g.177093242G>A) of the rs351855 SNP. The genotype-dependent phenotype is abolished in the FGFR4-deficient mice and is indistinguishable from the WT FGFR4-variant–expressing cohorts, indicative of enhanced rs351855 G>A-variant–specific STAT3 signaling in lymphoid organs.