Integrating the universe of regulatory cells in cancer. A major hurdle for successful immunotherapy

While most cancer immunotherapy strategies have focused on activating the immune system, growing evidence suggests that these therapies are thwarted by a complex immunosuppressive network at the tumor microenvironment. These immunosuppressive strategies include the selective expansion and recruitment of a diversity of regulatory immune cells, including tolerogenic immature and mature dendritic cells (DCs), plasmacytoid dendritic cells (pDCs), naturally-occurring and inducible regulatory T cells (Tregs and Tr1), myeloid-derived suppressor cells (MDSCs), tumor-associated macrophages (TAMs) and natural killer T (NKT) cells. Several studies using rodent models indicate that these regulatory cells may suppress tumor antigen-specific effector T cell responses through different, but partially overlapping mechanisms, and that their removal or functional inactivation promotes tumour rejection. In addition, the increasing number of studies of regulatory cells in patients with cancer also points to a role for these cells in disease progression. In this article we will briefly define the distinct role of different regulatory cell populations in tumor cell evasion of immune responses and will highlight potential avenues for immune intervention based on the removal and/or functional inactivation of these regulatory cell types.