T Regulatory Cells and Priming the Suppressive Tumor Microenvironment

Abstract

Treg play a central role in maintenance of self tolerance and homeostasis through suppression of self-reactive T cell populations. In addition to that role, Treg also survey cancers and suppress anti-tumor immune responses. Thus, understanding the unique attributes of Treg-tumor interactions may permit control of this pathologic suppression without interfering with homeostatic self-tolerance. This review will define the unique role of Treg in cancer growth, and the ways by which Treg inhibit a robust anti-tumor immune response. There will be specific focus placed on Treg homing to the tumor microenvironment (TME), TME formation of induced Treg (iTreg), mechanisms of suppression that underpin cancer immune escape, and trophic nonimmunologic effects of Treg on tumor cells.

Keywords: Treg; anti-tumor immunity; immunosuppression; metastasis; tumor microenvironment.

Figure 1

Tumor cell and Treg homing interactions. Treg home to the TME through interactions with chemokines/ligands produced by TME components including cancer cells. Some interactions are depicted including S1P:S1PR, CXCL12:CXCR4, CCL20:CCR6, CCL5:CCR5, CCL28:CCR10, and CCL2/22:CCR4.

Figure 2

Mechanisms of iTreg induction in the TME. iTreg are derived from naïve CD4+ T cells following exposure to a specific cytokine milieu. Constituents of the TME are capable of producing several factors that form iTreg which further promote immunosuppression and inhibition of the anti-tumor immune response. Specific factors that drive the formation of iTreg include TGFβ and IL-10; TGFβ and IL-10 transcripts have been isolated from tumor subtypes including ovarian, breast, renal cell, lung, and squamous cell carcinoma. Tumor derived exosomes contain IL-10, TGFβ, and Fas ligand capable of generating iTreg. IDO1 is ubiquitously expressed by components of the TME, including tumor cells, stromal cells, DCs, and MDSCs which drive induction of iTreg. Binding of tumor derived PD-L1/L2 to T cell PD-1 is implicated in development, maintenance, and suppressive function of iTreg through stabilization of FoxP3 expression.