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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 1867-1872 |
| Number of pages | 6 |
| Journal | Journal of Clinical Investigation |
| Volume | 128 |
| Issue number | 5 |
| DOIs | |
| State | Published - May 1 2018 |
| Externally published | Yes |
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ASJC Scopus subject areas
- Medicine(all)
Cite this
STAT3-enhancing germline mutations contribute to tumor-extrinsic immune evasion. / Kogan, Daniel; Grabner, Alexander; Yanucil, Christopher; Faul, Christian H; Ulaganathan, Vijay Kumar.
In: Journal of Clinical Investigation, Vol. 128, No. 5, 01.05.2018, p. 1867-1872.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - STAT3-enhancing germline mutations contribute to tumor-extrinsic immune evasion
AU - Kogan, Daniel
AU - Grabner, Alexander
AU - Yanucil, Christopher
AU - Faul, Christian H
AU - Ulaganathan, Vijay Kumar
PY - 2018/5/1
Y1 - 2018/5/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85046470434&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85046470434&partnerID=8YFLogxK
U2 - 10.1172/JCI96708
DO - 10.1172/JCI96708
M3 - Article
AN - SCOPUS:85046470434
VL - 128
SP - 1867
EP - 1872
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
SN - 0021-9738
IS - 5
ER -