Targeting T regulatory (T_reg) cells in immunotherapy-resistant cancers

Primary or secondary (i.e., acquired) resistance is a common occurrence in cancer patients and is often associated with high numbers of T regulatory (T_reg) cells (CD4⁺CD25⁺FOXP3⁺). The approval of ipilimumab and the development of similar pharmacological agents targeting cell surface proteins on T_reg cells demonstrates that such intervention may overcome resistance in cancer patients. Hence, the clinical development and subsequent approval of Cytotoxic T Lymphocyte Antigen-4 (CTLA-4) targeting agents can serve as a prototype for similar agents. Such new agents aspire to be highly specific and have a reduced toxicity profile while increasing effector T cell function or effector T/T regulatory (T_eff/T_reg) ratio. While clinical development with large molecules has shown the greatest advancement, small molecule inhibitors that target immunomodulation are increasingly entering early clinical investigation. These new small molecule inhibitors often target specific intracellular signaling pathways [e.g., phosphoinositide-3-kinase delta (PI3K-δ)] that play an important role in regulating the function of T_reg cells. This review will summarize the lessons currently applied to develop novel clinical agents that target T_reg cells.