Targeting regulatory T cells in cancer

Abstract

Infiltration of tumors by regulatory T cells confers growth and metastatic advantages by inhibiting antitumor immunity and by production of receptor activator of NF-κB (RANK) ligand, which may directly stimulate metastatic propagation of RANK-expressing cancer cells. Modulation of regulatory T cells can enhance the efficacy of cancer immunotherapy. Strategies include depletion, interference with function, inhibition of tumoral migration, and exploitation of T-cell plasticity. Problems with these strategies include a lack of specificity, resulting in depletion of antitumor effector T cells or global interruption of regulatory T cells, which may predispose to autoimmune diseases. Emerging technologies, such as RNA interference and tetramer-based targeting, may have the potential to improve selectivity and efficacy.

Figure 1

Targeting regulatory T cells in cancer. The central schematic depicts the main events involved in mounting an immune response to a tumour. Cells of both the innate and adaptive systems contribute (further details are provided in the text). T_Regs offer substantial resistance to this immune assault and thus four different approaches for reducing their immunosuppressive contribution are advanced (figure 1; A, B, C and D); depletion, inhibition of function, blockade of trafficking and modulation of T cell plasticity. Within each approach numerous existing and novel options for therapeutic manipulation are forwarded. Ab – antibody; DC – dendritic cell; IDO - indoleamine 2,3-dioxygenase; MDSCs – myeloid-derived suppressor cells; T_Reg – regulatory T cell.