Regulatory T cells (Tregs) are a subpopulation of T cells that modulate the immune system, generally suppressing the induction and proliferation of effector T cells (CD8+ cytotoxic T cells, Th1 and Th2 CD4+ T cells) to prevent pathological self-reactivity (i.e., autoimmune disease). Tregs express the biomarkers CD4, FOXP3, and CD25, and exert their immunosuppressive activity in a number of ways, including production of inhibitory cytokines, namely transforming growth factor β1 (TGF-β1).

In the context of cancer, Tregs suppress effector T cells and hinder the body's immune response against tumors. By suppressing inflammation, Tregs trigger cell proliferation and metastasis of cancer cells. Tregs seem to be preferentially trafficked to the tumor microenvironment.

Normally, Tregs make up around only 4% of CD4+ T cells, but they can make up as much as 20%-30% of the total CD4+ population in the tumor microenvironment. High levels of Tregs in the tumor microenvironment are associated with poor prognosis in many types of cancer, likely due to immunosuppression.

Because other types of effector T cells also express CD4 and CD25, Tregs have been notoriously difficult to study and differentiate from other T cells.

Learning about Tregs

Beginning in 2004, researchers from the University of Louvain de Duve Institute began studying the role of Tregs in how the immune system is blocked in tumors. The goal was to understand the function of immunosuppressive cells, which block the body's immune responses.

In 2009, the team discovered GARP, a molecule located on the surface of Tregs. Then in 2018, the researchers determined how the surface-bound latent form of TGF-β1 is activated. Within the Tregs, newly synthesized TGF-β1 homodimers form disulfide bonds with the transmembrane protein GARP, which acts to chaperone and orient the cytokine for activation at the cell surface.

Integrin αVβ8 interacts with the GARP:TGF-β1 complex leading to release of active TGF-β1 close to the surface of stimulated Tregs. These active TGF-β1 exert short-distance immunosuppressive effects on immune cells including effector T cells.

Now, the team led by Sophie Lucas, PhD, researcher at the de Duve Institute, is developing anti-GARP antibodies that block the release of active TGF-β1 by Tregs and increase the immune response against tumors.

Improving the effectiveness of preexisting immunotherapies

Remarkable progress has been made with monoclonal antibodies that block cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) or programmed cell death protein (PD-1) inhibitory pathways. However, a vast majority of patients do not respond to immunotherapies due to primary or acquired resistance to T-cell-mediated anti-tumor immunity.

Tregs play a significant role in antitumor immunity in many cancer types. To increase the efficacy of immunotherapies, researchers are searching for ways to block suppression of antitumor immunity by Tregs in cancer patients.

In the current paper, the researchers described how they constructed GARP:TGF-β1 monoclonal antibodies, derived from llamas, that block TGF-β1 activation by T cell receptor (TCR)-stimulated human Tregs. They demonstrated that the antibody blocked the release of TGF-β1 induced by TCR stimulation of mouse Tregs in vitro.

In vivo mouse models showed that inhibiting TGF-β1-dependent immunosuppression by intratumoral Tregs in cancer patients with anti-GARP:TGF-β1 monoclonal antibodies can increase the effectiveness of cancer immunotherapies. When given in combination with anti-PD-1 monoclonal antibodies, the treatment showed induced regression of tumors that are conventionally resistant to PD-1 immunotherapies.

The researchers found that GARP-expressing Tregs that produce TGF-β1 are required for the therapy to effectively block the activity of TGF-β1. This triggers tumor regression by inducing or reinvigorating inflammatory and cytolytic activities of anti-tumor CD8+ T cells that are already present in a given tumor.

Combining two complementary immunotherapy approaches, acting in different ways to modulate the immune system, can increase the overall effectiveness of the cancer treatment. While the current research was conducted in melanomas, the researchers suggested that this approach may be useful in several other cancers. In fact, a clinical trial is currently being conducted to evaluate the use of such antibodies for the treatment of advanced solid tumor cancers.

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