IL-6/JAK2/STAT3 axis mediates non-classical monocyte-induced Th17-like conversion of activated Tregs in acute myeloid leukemia patients.
7 affiliations
- 1Department of Clinical Laboratory, The First Affiliated Hospital of Anhui Medical University, #218 Jixi Road, Hefei, Anhui, 230032, China.
- 2Clinical Medical College of Anhui Medical University, Hefei, Anhui, China.
- 3Department of Blood Transfusion, The Third People's Hospital of Datong, Datong, Shanxi, China.
- 4Anhui Medical University, Hefei, Anhui, China.
- 5Department of Hematology, The First Affiliated Hospital of Anhui Medical University, #218 Jixi Road, Hefei, Anhui, 230032, China.
- 6Department of Hematology, The First Affiliated Hospital of Anhui Medical University, #218 Jixi Road, Hefei, Anhui, 230032, China. [email protected].
- 7Department of Clinical Laboratory, The First Affiliated Hospital of Anhui Medical University, #218 Jixi Road, Hefei, Anhui, 230032, China. [email protected].
Abstract
Purpose: Regulatory T cells (Tregs) promote tumor escape. Here we show CD45RA−FoxP3highCD4+ activated Tregs (aTreg, Fr. II) acquired a Th17-like phenotype in acute myeloid leukemia (AML). The primary objective of this study was to explore the specific roles of non-classical monocytes in regulating the increased Fr. II plasticity to Th17-like phenotype to form the immunosuppressive microenvironment.
Methods: We stratified phenotypically heterogeneous FoxP3⁺CD4⁺ T cells from AML patients into three subsets based on FoxP3 and CD45RA, aiming to dissect their functional diversity by flow cytometry. Flow cytometric sorting, co-culture assays, in vitro neutralization experiments, and JAK2 blockade assays were employed to demonstrate that non-classical monocytes induce Th17-like Fr. II cells through the IL-6/JAK2/STAT3 pathway.
Results: CD45RA−FoxP3high Fr. II, which performed a major inhibitory role in three FoxP3⁺CD4⁺ T subsets, were reduced in numbers but enhanced their immunosuppressive capacity in AML. Besides, Fr. II had a Th17-like phenotypic shift (marked by augmented IL-17 A and RORγt expression). Co-culture assays and in vitro neutralization experiments demonstrated that IL-6 secreted by non-classical monocytes regulates the conversion of Fr. II toward a Th17-like phenotype. Furthermore, JAK2 inhibitor reduced the phosphorylation of STAT3 and impaired Th17-like differentiation potency of Fr. II in AML patients. Notably, IL-17 A⁺ Fr. II were reduced after treatment.
Conclusions: Taken together, we found that non-classical monocytes drive the differentiation of Th17-like Fr. II via the IL-6/JAK2/STAT3 signaling pathway in AML. IL-17 A⁺ Fr. II may correlate with disease activity. Our finding reveals a new immune-evasion mechanism in AML, and offers a potential therapeutic target in the immunotherapy of AML.
Graphical Abstract: IL-6/JAK2/STAT3 axis mediates non-classical monocyte-induced Th17-like conversion of activated Tregs in acute myeloid leukemia patients. This study demonstrates that CD14-CD16+ nonclassical monocytes secrete IL-6, which binds to IL-6R on aTregs. This triggers downstream JAK2 phosphorylation, followed by STAT3 phosphorylation and subsequent RORγt expression, thereby stimulating aTregs to secrete IL-17 and further aggravating the severity of AML.
Supplementary Information: The online version contains supplementary material available at https://doi.org/10.1186/s12885-026-16619-6.
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BibTeX
@article{dai2026il6jak2stat3,
title = {{IL-6/JAK2/STAT3 axis mediates non-classical monocyte-induced Th17-like conversion of activated Tregs in acute myeloid leukemia patients.}},
author = {Xiaoran Dai and Yuanling Zheng and Xu Liu and Ruoyu Huang and Mei Fu and Meijuan Zheng and Yuanhong Xu and Jianyao Huang and Lu Zong},
journal = {BMC cancer},
year = {2026},
month = jul,
doi = {10.1186/s12885-026-16619-6},
url = {https://europepmc.org/article/MED/42958106},
note = {CC BY},
}
RIS
TY - JOUR
TI - IL-6/JAK2/STAT3 axis mediates non-classical monocyte-induced Th17-like conversion of activated Tregs in acute myeloid leukemia patients.
AU - Xiaoran Dai
AU - Yuanling Zheng
AU - Xu Liu
AU - Ruoyu Huang
AU - Mei Fu
AU - Meijuan Zheng
AU - Yuanhong Xu
AU - Jianyao Huang
AU - Lu Zong
PY - 2026
DA - 2026/07/28
JO - BMC cancer
DO - 10.1186/s12885-026-16619-6
UR - https://europepmc.org/article/MED/42958106
AB - Purpose: Regulatory T cells (Tregs) promote tumor escape. Here we show CD45RA−FoxP3highCD4+ activated Tregs (aTreg, Fr. II) acquired a Th17-like phenotype in acute myeloid leukemia (AML). The primary objective of this study was to explore the specific roles of non-classical monocytes in regulating the increased Fr. II plasticity to Th17-like phenotype to form the immunosuppressive microenvironment. Methods: We stratified phenotypically heterogeneous FoxP3⁺CD4⁺ T cells from AML patients into three subsets based on FoxP3 and CD45RA, aiming to dissect their functional diversity by flow cytometry. Flow cytometric sorting, co-culture assays, in vitro neutralization experiments, and JAK2 blockade assays were employed to demonstrate that non-classical monocytes induce Th17-like Fr. II cells through the IL-6/JAK2/STAT3 pathway. Results: CD45RA−FoxP3high Fr. II, which performed a major inhibitory role in three FoxP3⁺CD4⁺ T subsets, were reduced in numbers but enhanced their immunosuppressive capacity in AML. Besides, Fr. II had a Th17-like phenotypic shift (marked by augmented IL-17 A and RORγt expression). Co-culture assays and in vitro neutralization experiments demonstrated that IL-6 secreted by non-classical monocytes regulates the conversion of Fr. II toward a Th17-like phenotype. Furthermore, JAK2 inhibitor reduced the phosphorylation of STAT3 and impaired Th17-like differentiation potency of Fr. II in AML patients. Notably, IL-17 A⁺ Fr. II were reduced after treatment. Conclusions: Taken together, we found that non-classical monocytes drive the differentiation of Th17-like Fr. II via the IL-6/JAK2/STAT3 signaling pathway in AML. IL-17 A⁺ Fr. II may correlate with disease activity. Our finding reveals a new immune-evasion mechanism in AML, and offers a potential therapeutic target in the immunotherapy of AML. Graphical Abstract: IL-6/JAK2/STAT3 axis mediates non-classical monocyte-induced Th17-like conversion of activated Tregs in acute myeloid leukemia patients. This study demonstrates that CD14-CD16+ nonclassical monocytes secrete IL-6, which binds to IL-6R on aTregs. This triggers downstream JAK2 phosphorylation, followed by STAT3 phosphorylation and subsequent RORγt expression, thereby stimulating aTregs to secrete IL-17 and further aggravating the severity of AML. Supplementary Information: The online version contains supplementary material available at https://doi.org/10.1186/s12885-026-16619-6.
SN - 1471-2407
ER -