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Regulatory T Cells: Barriers of Immune Infiltration Into the Tumor Microenvironment

November 5, 2021

Experts from the Department of Immunology at the University of Pittsburgh School of Medicine recently published a review of research that examines the suppressive function of regulatory T cells (Tregs) and how they affect immune and non-immune cells outside and within the tumor microenvironment (TME). 

Tregs assist in the prevention of autoimmune diseases and are often used in combination with other immunotherapies to overcome the immunosuppressive environments of a tumor.

However, Tregs can also promote tumor growth by preventing extreme immune responses to limit tissue damage. 

Ellen N. Scott, PhD; Angela M. Gocher, PhD; Creg J. Workman, PhD; and Dario A. Vignali, PhD, from the Tumor Microenvironment Center at UPMC Hillman Cancer Center further explain how Tregs use their suppressive mechanisms to create barriers surrounding and within the TME. 

Tregs can act as anti-inflammatory intratumoral barriers by releasing “inhibitory receptors, inhibitory cytokines, and metabolic disruptors”1 that create a functional barrier within the TME to prevent the infiltration of effector cells. 

Another location of Tregs is the exterior area of the tumor, also known as the stroma, which is formed from non-tumor cells. These non-tumor cells on the outside of the TME include “fibroblasts that secrete proteins such as collagen and fibronectin that influence the migration of T cells.”1 The presence of collagen creates a stiffness surrounding the tumor, which greatly reduces the infiltration ability of the T cell. As a result, another functional and physical barrier to tumor immune infiltration is developed, leading to tumor growth and disease progression.

Tregs also act as barriers to tumor immune infiltration by increasing tumor angiogenesis, or the development of new blood vessels. Because the survival of the tumor is dependent on the blood supply into the TME, Tregs support an environment in which cancer cells can continue to develop. 

Lastly, Tregs serve as barriers in the stroma and periphery by “suppressing high endothelial venules formation, interfering with T cell activation, and suppressing the production of pro-inflammatory cytokines by effector T cells.”1

Ultimately, Tregs affect immune and non-immune cells both inside and outside of the TME. Numerous physical and biological barriers are created because of intratumoral Tregs that work to suppress the anti-tumor response.

It is recommended that future studies focus on examining Tregs through a spatial approach so that better insight into novel immunotherapies that destroy the barriers created by Tregs within the TME can be offered.


1. Scott EN, Gocher AM, Workman CJ, Vignali DAA. Regulatory T Cells: Barriers of Immune Infiltration Into the Tumor Microenvironment. Front Immunol. 2021;12:702726. Published 2021 Jun 10. doi:10.3389/fimmu.2021.702726