STAT3-enhancing germline mutations contribute to tumor-extrinsic immune evasion
Daniel Kogan, Alexander Grabner, Christopher Yanucil, Christian Faul, Vijay Kumar Ulaganathan
Daniel Kogan, Alexander Grabner, Christopher Yanucil, Christian Faul, Vijay Kumar Ulaganathan
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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 2

Rs351855 SNP-specific suppression of the CD8/Treg ratio in healthy tissues.

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Rs351855 SNP-specific suppression of the CD8/Treg ratio in healthy tissu...
(A) Analysis of CD8+ T cells in bone marrow, thymus, blood, lymph nodes, and spleen of 6- to 8-week-old Fgfr4rs351855–A/A and Fgfr4rs351855–G/G mice quantified by flow cytometry. Data represent the percentages of the total single-cell suspension (mean ± SEM, n = 5–8, **P < 0.01, NS = not significant). Statistical comparisons of groups were performed using 2-way ANOVA and Tukey’s t test with multiple comparisons. (B) Analysis of the CD8+ T cell content in the nonlymphoid parenchymal organs in Fgfr4rs351855–A/A and Fgfr4rs351855–G/G mice. Lung samples were from 5-month-old mice (mean ± SEM, n = 6–8, **P < 0.01) and breast tissue was taken from mice 3 months after pregnancy (mean ± SEM, n = 3–4, ***P < 0.001). Infiltrating cells were measured by preparing single-cell suspensions. (C) Analysis of CD4+CD25+FOXP3+ T cell numbers by flow cytometry of live splenocytes from Fgfr4rs351855–A/A and Fgfr4rs351855–G/G mice. Data represent the percentages of total single-cell suspensions (mean ± SEM, n = 5–8, *P < 0.05, ***P < 0.001). Statistical comparisons of groups were performed using 2-way ANOVA and Tukey’s t test with multiple comparisons. (D) Quantitative analysis of CD4+ and CD8+ cells in the thymus and spleen of 6- to 8-week-old Fgfr4+/+ and Fgfr4–/– mice and (E) CD4+CD25+FOXP3+ cells in the thymus and spleen of 6- to 8-week-old Fgfr4+/+ and Fgfr4–/– mice measured by flow cytometry. Data represent the percentages of total single-cell suspensions (mean ± SEM, n = 5–6, NS = not significant). Statistical comparisons of groups were performed using 2-way ANOVA and Tukey’s t test with multiple comparisons. All flow cytometry measurements on WT and mutant cohorts of mice were performed on the same day.