T-regulatory cells: key players in tumor immune escape and angiogenesis

Abstract

T-regulatory cells (Tregs) are found infiltrating tumors in a vast array of tumor types, and tumor-infiltrating Tregs are often associated with a poor clinical outcome. Tregs are potent immunosuppressive cells of the immune system that promote progression of cancer through their ability to limit antitumor immunity and promote angiogenesis. Here, we discuss the ways in which Tregs suppress the antitumor immune response and elaborate on our recent discovery that Tregs make significant direct contributions to tumor angiogenesis. Further, we highlight several current therapies aimed at eliminating Tregs in cancer patients. Given the multifaceted role of Tregs in cancer, a greater understanding of their functions will ultimately strengthen future therapies.

Figure 1. Role of Tregs in tumor progression

Tregs are recruited to tumors from the periphery by tumor-derived, hypoxia-induced CCL28, but also DC and tumor derived CCL22. Within the tumor microenvironment Tregs can be expanded by TGFβ and possibly IL-10, that can also convert CD4+ naïve precursors into induced Tregs. Tregs promote tumor progression by direct inhibition of antitumor effector CD4+ and CD8+ T cells through inhibitory cytokines, cytolysis and metabolic disruption. Further, Tregs recruited to hypoxic areas directly stimulate angiogenesis through production of VEGF. Tregs also indirectly encourage angiogenesis by blocking effector cell-derived angiostatic cytokines like IFNγ and CXCL-10.