Mixed lineage kinase 3 inhibition induces T cell activation and cytotoxicity

Significance The agents that inhibit mitogen-activated protein kinases (MAPKs) are reported to have antineoplastic efficacies; however, their impact on immune cells is not clearly defined. We identified that genetic loss/inhibition of a MAP3K member, MLK3, increases CD8+ T cell cytotoxicity via inhibition of a prolyl isomerase, Ppia, and nuclear translocation of NFATc1. The MLK3 inhibitor increased the tumor infiltration of cytotoxic T cells in an immune-competent mouse model of breast cancer. Similarly, the MLK3 inhibitor increased the cytotoxic T cell population in pan T cells isolated from breast cancer patients with metastatic disease. These results suggest that small-molecule inhibitor of MLK3 might have clinical usage even in the advanced stage of the disease, where tumor-induced immunosuppression is frequent.