Opening the Floodgates: The Role of SRC-3 in Regulatory T Cell Suppression

(Posted on Wednesday, November 15, 2023)

Opening the floodgates of the immune system could help the body fight cancer. As described in a previous installment, researchers at the Baylor College of Medicine successfully eliminated breast and prostate tumors in mice by altering the expression of a specific protein in their regulatory T cells. Peering deeper, this piece will explore the foundations of this discovery: what role SRC-3, the critical protein, plays in regulatory T cells and how this knowledge could build towards a treatment for solid tumors.

Regulatory T Cells and Immune Suppression

Regulatory T cells (or Tregs) are a subset of white blood cells that are necessary to maintain immune and prevent excessive responses from damaging the tissues.

The immune system, ever eager to wipe out its foes, can often overreact. When this happens, regulatory T cells suppress the overactive immune cells via several mechanisms, including the release of inhibiting cytokines, through cell-to-cell contact, and by disrupting metabolic pathways needed for cell activation and proliferation. Quelling rampant immune cells is particularly beneficial for limiting autoimmunity and chronic inflammation, as seen with diseases such as diabetes and rheumatoid arthritis.

While holding back other cells can be beneficial, this mechanism also allows solid tumors to grow unchecked. Tumors exploit regulatory T cells by recruiting them into the tumor microenvironment (TME). There, the regulatory T cells restrain immune cells that would otherwise recognize and attack the tumor.

What if we could release the floodgates? Reversing Treg suppression could free the deluge of immune cells to the tumor and restore the immune system’s anticancer activity. Examining the link between regulatory T cell suppression and cancer could lead to a viable therapeutic for solid tumors—one which other immunotherapies, such as CAR T therapy, struggle to address.

SRC-3, A Key Player 

Professor Bert W. O’Malley and colleagues have studied this topic for many years. Their investigations suggest that the key to understanding and wielding regulatory T cell suppression lies with a protein called steroid receptor coactivator 3.

Steroid receptor coactivator 3 (SRC-3, pronounced Sark Three) is a coactivator protein that influences gene expression. Although the role of SRC-3 in the immune system was largely undefined, O’Malley and colleagues later discovered that this protein is highly enriched in Treg cells and affects their function.

In the study, the team compared the immune activity of mice with and without SRC-3 through a gene knockout. These knockout mice display higher numbers of B cells and T cells in the lymph nodes, spleen and bone marrow; this observation is echoed when the spleens of the knockout mice are analyzed.

A list of 297 transcriptional coregulator proteins from the Nuclear Receptor Signaling Atlas (NURSA) was also assembled to determine what cells express SRC-3 the most. The team found that SRC-3 is the second-most correlated coregulator protein for Treg cells. To confirm this finding, the blood of three human donors was analyzed for transcript levels of the protein. Compared to other immune cells (specifically CD4” helper T cells), Tregs expressed much higher levels of SRC-3.

Additionally, the researchers discovered that perturbing SRC-3 function in human peripheral blood cells and Tregs had significant effects. SRC-3 inhibition using a drug called SI-2 leads to elevated proliferation of various blood cell populations. Additionally, it negatively impacts the induction of induced Tregs (iTregs) and hampers Treg suppressive activity when applied acutely, indicating that SRC-3 plays a role in Treg function.

Altogether, these findings reveal the crucial role of SRC-3 in Treg suppression in mice and humans, and how affecting SRC-3 expression changes Treg-associated genes. SRC-3, in response, may be a possible target for future cancer immunotherapies.

Ways to Open the Floodgates

A paper published in Breast Cancer Research continues this investigation by analyzing the connection between SRC-3 in Tregs and the tumor microenvironment. The researchers find that preventing SRC-3 expression, either through drug inhibition or gene knockouts, can impact the size and growth of breast tumors in mice.

Female mice received two types of breast cancer cells. Twice a day, the team administered SI-2, the SRC-3 inhibiting drug they developed, to the mice. The results show that the drug significantly suppresses the growth of breast cancer cells in mice. SI-2 treatment also alters the tumor microenvironment; the treatment increases the numbers of infiltrating CD4+, CD8+, and CD56+ cytotoxic immune cells in the breast tumors. This suggests that the SI-2 drug can inhibit SRC-3 expression in Tregs, allowing other immune cells to act and clear the tumor.

When analyzing the effect of SRC-3 knockdown, the authors observed that the gene knockout significantly inhibited tumor progression in mice with fully functioning immune systems. Mice that had the knockout but lacked fully functioning immune systems did not experience the same effect, implying that SRC-3 knockout suppression depends on the host immune system.

Both SI-2 treatment and SRC-3 knockout changed the cytokine profile in breast tumors, likely contributing to tumor growth suppression. Arguably, it is more effective to knock out SRC-3 protein expression than to use drug inhibitors. A gene knockout isolates the reaction to specific cells; drug inhibitors, in comparison, must circulate the system.

Implications for Cancer

Baylor College of Medicine researchers unveil a promising avenue for combating solid tumors by targeting SRC-3. SRC-3 is a pivotal protein in regulatory T cell suppression for both mice and humans. By inhibiting SRC-3 expression through drug intervention or gene knockout, the floodgates of the immune system could be released, allowing it to unleash its full anticancer potential. This research inches towards a future where solid tumors may no longer thrive unchecked, and the immune system becomes a potent weapon against cancer.

This article was originally published on Forbes and can be read online here.