FLT3LG induction by γ-chain cytokine promotes regulatory-like CD4+ T cell features in breast cancer
- 1Department of Biochemistry, BK21 Plus and The Research Institute for Veterinary Science, College of Veterinary Medicine, Seoul National University, Gwanak-ro1, Gwanak-gu, Seoul, 08826 Republic of Korea
- 2Comparative Medicine Disease Research Center, Seoul National University, Seoul, 08826 Republic of Korea
- 3Present Address: Department of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, CA USA
Abstract
Regulatory and dysfunctional CD4+ T cell states contribute to immune evasion in breast cancer (BC), but the molecular programs associated with these phenotypes remain incompletely understood. Here, we identify FLT3 ligand (FLT3LG) as a γ-chain (γc) cytokine-responsive factor enriched in CD4+ T cells of BC. Public transcriptomic and scRNA-seq analyses showed that FLT3LG expression was linked to Treg-enriched immune regulatory signatures. In Jurkat T cells, FLT3LG overexpression (OE) increased regulatory markers and inhibitory receptors while reducing effector cytokine expression and proliferative capacity, consistent with a regulatory-like and reduced effector phenotype rather than bona fide Treg differentiation. In BC co-culture models, HER2+ BC cell lines induced FLT3LG and FOXP3 expression in Jurkat and primary human T cells. FLT3LG-OE T cells were further associated with increased Ki-67 expression and reduced apoptosis in co-cultured BC cells, as well as altered CFSE profiles of primary responder T cells. Mechanistically, γc cytokines induced FLT3LG expression through STAT5-dependent signaling. In a syngeneic mammary tumor model, FLT3LG expression increased in CD4+ T cells during tumor progression, particularly within the Treg subset. Consistently, clinical dataset analyses showed that high FLT3LG expression was associated with poor outcomes in HER2+ and highly proliferative BC contexts. Together, these findings reveal a γc cytokine-STAT5-FLT3LG regulatory circuit linked to CD4+ T cell immunoregulation in BC.
Graphical abstract:
Supplementary Information: The online version contains supplementary material available at https://doi.org/10.1007/s00262-026-04492-y.
Related
- Hypoxia-inducible factor 2-alpha promotes fitness of cytokine-activated human natural killer cells
- Association of regulatory B, T cells and cytokine production with disease stage in non-small cell lung cancer patients: prospective case control study.
- TSLP promotes GATA3-expressing effector regulatory T cells via DC2 derived from transitional DCs
- Conserved and Promoter-Specific Cis-Regulatory Features of Digestion-Associated Chitinase Genes in Droseraceae
- A heat-induced HagF-HrcA regulatory loop promotes chlamydial fitness and infectious progeny yield under stress
BibTeX
@article{im2026flt3lg,
title = {{FLT3LG induction by γ-chain cytokine promotes regulatory-like CD4+ T cell features in breast cancer}},
author = {Yeo-Jin Im and Hyeon-Ji Hwang and Chae-Yi Kim and Je-Yoel Cho},
journal = {Cancer Immunology, Immunotherapy : CII},
year = {2026},
month = jul,
doi = {10.1007/s00262-026-04492-y},
url = {https://doi.org/10.1007/s00262-026-04492-y},
note = {CC BY-NC-ND 4.0},
}
RIS
TY - JOUR
TI - FLT3LG induction by γ-chain cytokine promotes regulatory-like CD4+ T cell features in breast cancer
AU - Yeo-Jin Im
AU - Hyeon-Ji Hwang
AU - Chae-Yi Kim
AU - Je-Yoel Cho
PY - 2026
DA - 2026/07/28
JO - Cancer Immunology, Immunotherapy : CII
DO - 10.1007/s00262-026-04492-y
UR - https://doi.org/10.1007/s00262-026-04492-y
AB - Regulatory and dysfunctional CD4+ T cell states contribute to immune evasion in breast cancer (BC), but the molecular programs associated with these phenotypes remain incompletely understood. Here, we identify FLT3 ligand (FLT3LG) as a γ-chain (γc) cytokine-responsive factor enriched in CD4+ T cells of BC. Public transcriptomic and scRNA-seq analyses showed that FLT3LG expression was linked to Treg-enriched immune regulatory signatures. In Jurkat T cells, FLT3LG overexpression (OE) increased regulatory markers and inhibitory receptors while reducing effector cytokine expression and proliferative capacity, consistent with a regulatory-like and reduced effector phenotype rather than bona fide Treg differentiation. In BC co-culture models, HER2+ BC cell lines induced FLT3LG and FOXP3 expression in Jurkat and primary human T cells. FLT3LG-OE T cells were further associated with increased Ki-67 expression and reduced apoptosis in co-cultured BC cells, as well as altered CFSE profiles of primary responder T cells. Mechanistically, γc cytokines induced FLT3LG expression through STAT5-dependent signaling. In a syngeneic mammary tumor model, FLT3LG expression increased in CD4+ T cells during tumor progression, particularly within the Treg subset. Consistently, clinical dataset analyses showed that high FLT3LG expression was associated with poor outcomes in HER2+ and highly proliferative BC contexts. Together, these findings reveal a γc cytokine-STAT5-FLT3LG regulatory circuit linked to CD4+ T cell immunoregulation in BC. Graphical abstract: Supplementary Information: The online version contains supplementary material available at https://doi.org/10.1007/s00262-026-04492-y.
SN - 0340-7004
SN - 1432-0851
ER -