Deciphering Regulatory T-Cell Dynamics in Cancer Immunotherapy: Mechanisms, Implications, and Therapeutic Innovations

Abstract

This Review explores how tumor-associated regulatory cells (Tregs) affect cancer immunotherapy. It shows how Tregs play a role in keeping the immune system in check, how cancers grow, and how well immunotherapy work. Tregs use many ways to suppress the immune system, and these ways are affected by the tumor microenvironment (TME). New approaches to cancer therapy are showing promise, such as targeting Treg checkpoint receptors precisely and using Fc-engineered antibodies. It is important to tailor treatments to each patient's TME in order to provide personalized care. Understanding Treg biology is essential for creating effective cancer treatments and improving the long-term outcomes of immunotherapy.

Figure 1

(A) Phenotypical markers of Tregs have been extensively studied. CD4, CD25, and FOXP3 are commonly used markers to identify Tregs. Other markers, such as CTL44, TGF-BR, TIM-3 Helios, CCR5, and CD3, have also been reported to be expressed by Tregs at different levels. However, none of these markers are specific to Tregs, and their expression can also be found on other T-cell subsets or activated T cells. Therefore, the combination of multiple markers is often used to improve the identification and isolation of Tregs. Additionally, the expression of markers may vary depending on the tissue or the degree of inflammation, making it important to consider the specific context when studying Tregs. (B) Tregs obtained from the thymus show a differentiated phenotype with high expression of CD25, Foxp3, and CD4. They also exhibit a higher frequency of IL-10-secreting cells and a greater suppressive capacity compared to blood-derived Tregs.

Figure 2

Peripheral Treg cells, also known as peripherally derived Tregs, play a crucial role in maintaining immune homeostasis in the intestine. The function and T cell receptor repertoire of peripheral Treg cells differ from those of thymically derived Treg cells, suggesting a specialized role in certain inflammatory settings.

Figure 3

The TME consists of various components, such as a hypoxic tumor cell, an apoptosis cell, macrophages, exhausted lymphocytes, Treg, DC, a cancer cell, a NK cell, and a fibroblast. These noncancerous cells in the TME play a crucial role in tumor survival, propagation, and progression through multidirectional interactions.

Figure 4

Treg suppression is an important aspect of immune regulation. Various protocols can be used to analyze the function of Tregs in vitro. Tregs can potentiate group 2 innate lymphoid cell (ILC2) functions through platelet adhesion.

Figure 5

Key approaches and target enzymes: Immune checkpoint blockade involves the use of therapeutic antibodies to disrupt negative immune regulatory checkpoints and unleash antitumor immune responses.

Figure 6

Induction of naive T cells involve the activation of these cells in response to viral infection or interaction with specific ligands. Naïve T cells are unactivated lymphocytes that circulate through the body’s secondary lymphoid tissues awaiting contact with APCs. Upon encountering an antigen displayed on an APC, the T cell receptor (TCR) engages with the antigen-MHC complex, leading to activation if accompanied by costimulatory signals. Activated naïve T cells differentiate into Teffs or memory T cells, providing long-lasting immunity.

Figure 7

Overview of ROS activity and Treg functions in cancer immunotherapy: Moderate levels of ROS are necessary for efficient T cell immunity, while excessive ROS can lead to an immunosuppressive TME. Tregs are involved in immune suppression and can promote tumor development and progression by inhibiting antitumor immune responses. Targeting Tregs has emerged as a promising strategy for cancer immunotherapy, with several approaches targeting Treg-specific markers or functions.