IL-21 boosts T cell-therapy efficacy for solid tumors by enhancing mitochondrial Ca2+-mediated motility of effector CD8+ T cells

Cell motility, characterized by random walk and exploratory search movement, enables effector CD8+ T cells to search for sparse antigen-specific cancer targets within a tumor. This is of special relevance for treatment of solid cancers with adoptive T-cell receptor (TCR) T-cell therapy, where administered effector CD8+ T cells recognize specific MHC-I-presented antigens. Cell motility requires cytoskeleton remodeling to facilitate shape changes and movement. Herein, we show that increased mitochondrial Ca2+ levels are essential to reduce cytoskeleton stiffness of effector CD8+ T cells, leading to acquisition of a polarized shape and high motility. IL-21, but not IL-7 or IL-15, was able to raise mitochondrial Ca2+ levels in effector CD8+ T cells and increase their motility without affecting survival and proliferation. This increase in mitochondrial Ca2+ levels triggered by IL-21 was driven by sustaining mitochondrial membrane potential through mitochondrial STAT3, independently of its transcriptional activity. Enhanced motility of effector CD8+ T cells led to a superior killing efficacy of antigen-specific melanoma cells in vitro. Furthermore, enhanced mitochondrial Ca2+-mediated motility of adoptive TCR-specific effector CD8+ T cells resulted in a superior antitumor efficacy of this treatment against solid tumors in vivo. Thus, enhancing effector CD8+ T-cell motility is a promising strategy to boost efficacy of adoptive T-cell therapies against solid tumors.