Tumor resident regulatory T cells

Abstract

The immune system mediates powerful effector mechanisms to protect against a diversity of pathogens and equally as important regulatory functions, to limit collateral damage of inflammation, prevent misguided immune responses to "self", and promote tissue repair. Inadequate regulatory control can lead to a variety of inflammatory disorders including autoimmunity, metabolic syndrome, allergies, and progression of malignancies. Cancers evolve complex mechanisms to thwart immune eradication including coopting normal host regulatory processes. This is most evident in the analysis of tumor infiltrating lymphocytes (TILs), where a preponderance of immunosuppressive immune cells, such as regulatory T (Treg) cells are found. Treg cells express the X-chromosome linked transcription factor Foxp3 and play a crucial role in maintaining immune homeostasis by suppressing inflammatory responses in diverse biological settings. Treg cells in the tumor microenvironment promote tumor development and progression by dampening anti-tumor immune responses, directly supporting the survival of transformed cells through elaboration of growth factors, and interacting with accessory cells in tumors such as fibroblasts and endothelial cells. Current insights into the phenotype and function of tumor associated Treg cells have opened up opportunities for their selective targeting in cancer with the goal of alleviating their suppression of anti-tumor immune responses while maintaining overall immune homeostasis. Here, we review Treg cell biology in the context of the tumor microenvironment (TME), and the important role they play in cancer immunotherapy.

Keywords: Anti-tumor immunity; Cancer immunotherapy; FOXP3; Immune homeostasis; Regulatory T cells; Treg suppression; Tumor microenvironment.

Figure 1.. Treg cell suppressor functions

Treg cells express and elaborate several molecules that mediate their suppressive activity. Amphiregulin (Areg) promotes the growth and repair of supportive stromal elements. High levels of the IL2Ra chain CD25 mediates the depletion of IL-2. Treg cells express inhibitory molecules such as CTLA-4, which inhibit DCs activation and maturation through CD80/CD86 signaling. Treg cells also secrete suppressive cytokines such as TFGβ IL-10 and EBI3. The cell surface receptor LAG-3 engages MHCII complexes and can inhibit the function of DCs. CD39 and CD73 are ecto-nucleases which contribute to creating a suppressive environment by converting ATP to adenosine. Finally, Treg cells also can directly lyse their targets through the secretion of granzyme and perforin.

Figure 2.. Treg cell adaptation in the TME

Several factors contribute to the increased frequency of Treg cells in the TME as compared to normal tissues. Treg cells in the TME may confer tolerance through suppression of DCs. Treg cells express chemokine receptors and are recruited to the tumors by a gradient of chemokines produced by various cells in the TME. TME suppressive molecules such as TGFβ promote the local conversion of CD4+ cells to Foxp3+ Treg cells. Stromal cell secreted IDO promotes Treg stability by inhibiting the production of IL-6 by DCs. Treg cells are metabolically adapted to the TME and promote the suppressive environment by facilitating the conversion of ATP to adenosine. DC: dendritic cell; Neu: neutrophil; Caf: cancer associate fibroblast; Mac: macrophage.