CCL2 conditionally determines CCL22-dependent Th2-accumulation during TGF-β-induced breast cancer progression

[Display omitted] •TGF-β conditionally regulates CCL2 and CCL5 expression in breast cancer.•CCL2 induces macrophages and/or monocytes for elevated CCL22 secretion.•CCL22 favors Th2-cell accumulation within tumor microenvironment.•HighCCL2-LowCCL5 shifts Th1-Th2 balance towards Th2 cells during cancer progression. We investigated expressions of −CC chemokine ligand 2 (CCL2) and CCL5 in tumor samples from 147 breast cancer (BCa) patients and correlated with transforming growth factor-β (TGF-β) expression. We observed an inverse correlation of TGF-β expression with CCL2, CCL5 expression in early stages of BCa. On contrary, in late stages, CCL2, not CCL5, expression was found to be directly proportional with TGF-β expression. TGF-β stimulated MDA-MB-231 cells to express CCL2, however, downregulated both CCL2 and CCL5 in MCF-7. Interestingly, a significant swing of Th1-Th2 ratio towards Th2 is seen within the primary tumors expressing moderate/high-CCL2-low/negative-CCL5. We observed that CCL2-CCR2 interaction induces monocytes/macrophages to secrete Th2-attracting chemokine CCL22 in vitro. Therefore, CCL2 secreted from the tumor microenvironment may attract and interact with monocytes/macrophages, and favor Th2 accumulation by inducing CCL22 secretion. Study in 4T1-BALB/c BCa mouse model demonstrated significant (p