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

Abstract

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.

Keywords: cancer; immune infiltration; regulatory T cells (Treg); stroma; tumor microenvironment; vasculature.

Figure 1

Overview of suppressive mechanisms used by T_regs to create barriers to immune infiltration into tumors. Panel (A) Within the TME, T_regs utilize inhibitory receptors (TIM-3, TIGIT, PD1, and LAG-3), inhibitory cytokines (TGFβ, IL-10, and IL-35), DC modulation (via CTLA-4 and LAG-3), and metabolic disruption (via CD39/CD73) to suppress the anti-tumor T cell response. (B) T_reg-derived TGFβ induces cancer-associated fibroblast (CAF) development that increases extracellular matrix (ECM) production and deposition within the peritumoral space (stroma) to inhibit effector T cell migration. (C) T_regs block entry of effector T cells through preventing proper cytokine signals that promote high endothelial venule (HEV) formation as well as production of inhibitory IL-10 and VEGF to promote dysregulated angiogenesis. (D) In the periphery and secondary lymphoid organs (SLO), T_regs can modulate DC maturity and induce apoptosis to prevent proper effector T cell activation.