Mixed lineage kinase 3 inhibition induces T cell activation and cytotoxicity
Sandeep Kumar, Sunil Kumar Singh, Navin Viswakarma, Gautam Sondarva, Rakesh Sathish Nair, Periannan Sethupathi, Subhash C. Sinha, Rajyasree Emmadi, Kent Hoskins, Oana C. Danciu, Gregory R. J. Thatcher, Basabi Rana, Ajay Rana
Abstract
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.