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

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

Research output: Contribution to journalArticle

3 Citations (Scopus)

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 languageEnglish (US)
Pages (from-to)1867-1872
Number of pages6
JournalJournal of Clinical Investigation
Volume128
Issue number5
DOIs
StatePublished - May 1 2018
Externally publishedYes

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Tumor Escape
STAT3 Transcription Factor
Germ-Line Mutation
Neoplasms
Immune Evasion
Transgenic Mice
Regulatory T-Lymphocytes
Immunosuppressive Agents
Knockout Mice
Single Nucleotide Polymorphism
Lung Neoplasms
Genotype
Breast Neoplasms
T-Lymphocytes

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Kogan, D., Grabner, A., Yanucil, C., Faul, C. H., & Ulaganathan, V. K. (2018). STAT3-enhancing germline mutations contribute to tumor-extrinsic immune evasion. Journal of Clinical Investigation, 128(5), 1867-1872. https://doi.org/10.1172/JCI96708

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 journalArticle

Kogan, D, Grabner, A, Yanucil, C, Faul, CH & Ulaganathan, VK 2018, 'STAT3-enhancing germline mutations contribute to tumor-extrinsic immune evasion', Journal of Clinical Investigation, vol. 128, no. 5, pp. 1867-1872. https://doi.org/10.1172/JCI96708
Kogan, Daniel ; Grabner, Alexander ; Yanucil, Christopher ; Faul, Christian H ; Ulaganathan, Vijay Kumar. / STAT3-enhancing germline mutations contribute to tumor-extrinsic immune evasion. In: Journal of Clinical Investigation. 2018 ; Vol. 128, No. 5. pp. 1867-1872.
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