Treg Cell Therapeutic Strategies for Breast Cancer: Holistic to Local Aspects

Abstract

Regulatory T cells (Tregs) play a key role in maintaining immune homeostasis and preventing autoimmunity through their immunosuppressive function. There have been numerous reports confirming that high levels of Tregs in the tumor microenvironment (TME) are associated with a poor prognosis, highlighting their role in promoting an immunosuppressive environment. In breast cancer (BC), Tregs interact with cancer cells, ultimately leading to the suppression of immune surveillance and promoting tumor progression. This review discusses the dual role of Tregs in breast cancer, and explores the controversies and therapeutic potential associated with targeting these cells. Researchers are investigating various strategies to deplete or inhibit Tregs, such as immune checkpoint inhibitors, cytokine antagonists, and metabolic inhibition. However, the heterogeneity of Tregs and the variable precision of treatments pose significant challenges. Understanding the functional diversity of Tregs and the latest advances in targeted therapies is critical for the development of effective therapies. This review highlights the latest approaches to Tregs for BC treatment that both attenuate Treg-mediated immunosuppression in tumors and maintain immune tolerance, and advocates precise combination therapy strategies to optimize breast cancer outcomes.

Keywords: breast cancer; regulatory T cells; treatment.

Figure 1

Tregs function differently in the tumor microenvironment and peripheral tissues (created with BioRender.com).

Figure 2

Source and classification of Treg cells: nTregs and tTregs secreted by naive CD4⁺ T cells in the thymus, and secreted in the periphery as iTregs and pTregs. tTregs produce an inhibitory effect on Teff, either through antigenic stimulation (IL-10, transforming growth factor (TGF-β), PD-L1, etc.) or through direct contact with CTLA4.

Figure 3

Plasticity of Tregs, in relation to Th cells in the immune system.

Figure 4

BC interacts with Tregs in the TME. Tumor tissue in the TME recruits Tregs via a variety of chemokines, leading to local Treg enrichment in the tumor (e.g., CCL17/22, CCL5, CCL1-CCR8, etc.). Tregs inhibit Teff through surface antibodies (CTLA-4, PD-1, etc.) and by secreting TGF-β and cytokines (IL-10, IL-35, etc.). Metabolites associated with Treg cells (ADO, IDO, lactate) can promote Treg activity, creating a positive feedback loop. Tregs also control NK activation in lymph nodes. VEGF attracts Foxp3⁺ Treg with high Nrp-1 expression to achieve a tumor immune escape. ASC-EV and Treg-EV promote each other.

Figure 5

Treg removal or suppression methods in BC (created with BioRender.com).

Figure 6

Schematic representation of the structure and composition of Treg-Evs. Treg-EV endonucleic acids: DNA, mRNA, miRNA, lncRNA and circRNA. Common proteins of Treg-EVs are classified as membrane proteins: TCR/CD3, membrane transporter proteins (flotillin), fusion proteins (annnexins), tetratransmembrane proteins (CD63), cell adhesion-associated proteins (integrins) and lysosomal-related membrane proteins (LAMP-1). Intracellular proteins: heat shock protein (HSP70), endosomal sorting complex for transport (ESCRT), auxiliary protein components (TSG101), GAPDH and cell-specific proteins related to Treg cell surface proteins (e.g., CD4, CD25, CTLA-4, CD73, CD81, etc.).