Regulatory T Cells: Barriers of Immune Infiltration Into the Tumor Microenvironment

Regulatory T cells (T_regs) are key immunosuppressive cells that promote tumor growth by hindering the effector immune response. T_regs utilize multiple suppressive mechanisms to inhibit pro-inflammatory responses within the tumor microenvironment (TME) by inhibition of effector function and immune cell migration, secretion of inhibitory cytokines, metabolic disruption and promotion of metastasis. In turn, T_regs are being targeted in the clinic either alone or in combination with other immunotherapies, in efforts to overcome the immunosuppressive TME and increase anti-tumor effects. However, it is now appreciated that T_regs not only suppress cells intratumorally via direct engagement, but also serve as key interactors in the peritumor, stroma, vasculature and lymphatics to limit anti-tumor immune responses prior to tumor infiltration. We will review the suppressive mechanisms that T_regs utilize to alter immune and non-immune cells outside and within the TME and discuss how these mechanisms collectively allow T_regs to create and promote a physical and biological barrier, resulting in an immune-excluded or limited tumor microenvironment.