Tumor cell derived CCL20 exacerbates the immunosuppressive microenvironment by recruiting CCR6⁺ Tregs in pancreatic...

Pancreatic cancer has a dismal prognosis, largely due to resistance to all current therapeutic modalities, including prevailing immunotherapy. Deciphering the mechanisms underlying the immunosuppressive tumor microenvironment is pivotal for developing effective therapeutic strategies. In this study, we found that the expression of CCL20 is negatively correlated with the infiltration of CD8⁺ T cells, and consistently, patients with higher CCL20 expression have a worse prognosis. CCL20, as a secreted ligand protein regulated by SP5, can bind to its cognate receptor CCR6 in the tumor microenvironment and is mainly produced by tumor cells, as confirmed by single-cell RNA sequencing and immunofluorescence staining of tumor tissues. Compared with CCL20 wild-type tumors, CCL20 knockout tumors exhibited impaired growth, decreased infiltration of CCR6⁺ Tregs, and concomitantly increased infiltration of CD8⁺ T cells. Importantly, this altered immune infiltration phenotype was abolished in Treg-specific CCR6 knockout mice. Furthermore, CCR6 inhibition potentiated the efficacy of anti-PD1 immune checkpoint blockade. Taken together, our data demonstrate that tumor cell-derived CCL20 shapes an immunosuppressive microenvironment in pancreatic cancer by recruiting CCR6⁺ Tregs, suggesting that targeting the CCL20-CCR6 axis offers a promising therapeutic strategy, particularly when combined with immune checkpoint blockade.