The role of the CXCL10-CXCR3 axis in directing the biological function of anti-tumor CD8+ T cells

Chemokines are small (~8-14 kDa) secreted proteins, structurally similar to cytokines. They regulate cell trafficking through interactions with a subset of seven-transmembrane G protein-coupled receptors (GPCRs). Almost 20 years ago in attempt to comprehend what makes few chemokines, and not many others, key targets for neutralization in inflammatory- autoimmunity we raised the hypothesis that few chemokines should be considered as “Driver chemokines” as aside for their chemotactic properties they also direct the biological function of immune cells. Our major study focused on CXCR3 and its ligands. CXCR3 is a chemokine receptor with three known ligands CXCL9, CXCL10 and CXCL11. Seventeen years ago, we have reported that CXCL10 polarizes and potentiates effector CD4+ T cells, thus its neutralization suppresses autoimmunity. Later we observed that CXCL11 induces FOXp3-negative T cells to restrain inflammation and thus the CXCL10/CXCL11 balance regulates the dynamic of adaptive immunity. Focusing on CXCL10 we further examined its role in cancer diseases. While vast majority of chemokines that are produced by cancer cells support tumor development either directly or by recruiting myeloid derived suppressor cells, and tumor associated macrophages to support tumor progression, CXCL10 suppresses tumor growth. On the mechanistic basis we found that this includes direct suppression of tumor growth, and potentiation of anti-tumor CD8+ T cells.