TGF‐β1 secreted by Tregs in lymph nodes promotes breast cancer malignancy via up‐regulation of IL‐17RB

Lymph node (LN) metastasis is commonly associated with systemic distant organ metastasis in human breast cancer and is an important prognostic predictor for survival of breast cancer patients. However, whether tumor‐draining LNs (TDLNs) play a significant role in modulating the malignancy of cancer cells for distant metastasis remains controversial. Using a syngeneic mouse mammary tumor model, we found that breast tumor cells derived from TDLN have higher malignancy and removal of TDLNs significantly reduced distant metastasis. Up‐regulation of oncogenic Il‐17rb in cancer cells derived from TDLNs contributes to their malignancy. TGF‐β1 secreted from regulatory T cells (Tregs) in the TDLNs mediated the up‐regulation of Il‐17rb through downstream Smad2/3/4 signaling. These phenotypes can be abolished by TGF‐β1 neutralization or depletion of Tregs. Consistently, clinical data showed that the up‐regulation of IL‐17RB in cancer cells from LN metastases correlated with the increased prevalence of Tregs as well as the aggressive growth of tumors in mouse xenograft assay. Together, these results indicate that Tregs in TDLNs play an important role in modulating the malignancy of breast cancer cells for distant metastasis. Blocking IL‐17RB expression could therefore be a potential approach to curb the process. Synopsis Treg‐secreted TGF‐β1 in the tumor‐draining LN (TDLN) microenvironment up‐regulates IL‐17RB expression in breast cancer cells, thereby enhancing their metastatic potential. Breast cancer cells isolated from TDLN displayed aggressive phenotypes; removal of TDLN reduced distant organ metastasis. Tregs in TDLN was the major cell type contributing to the enhanced malignancy of breast cancer cells. TGF‐β1 secreted from Tregs in TDLN up‐regulated IL‐17RB expression in breast cancer cells. Up‐regulation of IL‐17RB by TGF‐β1 occurred through Smad2/3/4 signal pathway. Graphical Abstract Treg‐secreted TGF‐β1 in the tumor‐draining LN (TDLN) microenvironment up‐regulates IL‐17RB expression in breast cancer cells, thereby enhancing their metastatic potential.