Effector/Memory but Not Naive Regulatory T Cells Are Responsible for the Loss of Concomitant Tumor Immunity1

The phenomenon of concomitant tumor immunity involves a tumor-bearing host rejecting another similar tumor at a distant site and suggests the existence of tumor-specific immunity. Loss of this immunity may contribute to tumor metastasis. However, mechanisms underlying the loss of concomitant immunity are largely unknown. We set up a concomitant tumor immunity model in which this immunity is gradually lost as the primary tumor progresses. We found that CD8+ T cells, especially tumor-infiltrating CD8+ T cells, from mice that lost concomitant tumor immunity, possessed potent antitumor properties and strongly expressed effector molecules. Furthermore, effector/memory regulatory T cells (Treg cells, CD103+CD4+Foxp3+ T cells) increased as the primary tumor progressed. They initially accumulated around the tumor and in the spleen at later points. Not only did these cells more greatly express killing molecules, they also suppressed the functions of tumor-bearing CD8+ T cells in vitro and in vivo. Finally, we show that these effector/memory Treg cells inhibit concomitant tumor immunity in vivo. Taken together, data suggest that effector/memory Treg cells are responsible for the loss of concomitant tumor immunity associated with tumor progression.