A recent study conducted by the US authors aimed to comprehend the specific function of steroid receptor coactivator 3 (SRC-3) within the regulatory T cell (Tregs) compartment, with a particular emphasis on tumor evasion of the immune system. The findings showed that SRC-3 is a key modulator of Tregs–mediated tumor escape. A disruption in the expression of SRC-3 in Tregs resulted in a complete tumor elimination in aggressive syngeneic breast cancer mouse models.
SRC-3 is a pleiotropic coactivator that interacts with a wide range of transcription factors. Given the broad control of SRC-3 on gene expression, the deletion of SRC-3 could change the expression of a wide range of key genes involved in efferent and afferent Treg signaling, according to the authors. It is noteworthy that SRC-3 is the second most highly expressed transcriptional coactivator in Tregs and B cells, which suggests that it plays an important role in the regulation of Treg-mediated immune suppression.
Treg cells have been demonstrated to regulate various facets of immune responses. Tregs constrain effector immune cell proliferation and function through a number of mechanisms. Activated Tregs produce several anti-inflammatory cytokines, such as interleukin (IL)-10, IL-35, and transforming growth factor-beta (TGF-β), which suppress cytotoxic effector immune cells. This creates a negative feedback mechanism to limit the immune response. Tregs also produce perforin and granzyme B, which can induce apoptosis in cytotoxic effector T cells, inhibit natural killer cell proliferation, and suppress the production of interferon-γ (IFN-γ ) through their secretion of TGF-β.
Furthermore, Tregs are essential in restraining immune responses that maintain the immune homeostasis necessary to prevent autoimmune disease. A loss of Treg function can lead to the development of chronic autoimmune diseases.
Some previous studies have demonstrated a critical role of SRC-3 in generating a tumor-promoting immune microenvironment that enhances breast tumor progression in immune-intact mice. The inhibition of SRC-3 by an SRC-3 small molecular inhibitor and the knockdown of SRC-3 in breast cancer cells generated a tumor-suppressive immune microenvironment by increasing the number of tumor-infiltrating cytotoxic immune cells and IFN-γ.
About the study
Using genetically engineered tamoxifen-inducible Treg-cell-specific SRC-3 knockout (KO) female mice, the research team showed that a disruption in the expression of SRC-3 in Tregs resulted in a complete tumor elimination in aggressive syngeneic breast cancer models. Similar results were observed in a syngeneic model of prostate cancer. A subsequent injection of additional E0771 cancer cells into these mice demonstrated continued resistance to tumor development without the need for tamoxifen induction to produce additional SRC-3 KO Tregs. The disruption of Treg SRC-3 expression significantly altered the tumor-immune microenvironment in a way that supports tumor destruction by an animal’s own immune system.
In addition, a single adoptive cell transfer of SRC-3 KO Tregs into wild-type E0771 tumor-bearing mice resulted in the regression of tumors to undetectable levels by generating potent antitumor immunity with a durable effect that prevents tumor reoccurrence. After tumor clearance to undetectable levels by adoptive cell transfer with SRC-3 KO Tregs, recurrence was not detected for at least 215 days.
SRC-3 KO Tregs were highly proliferative and were preferentially infiltrated into breast tumors by activating the ligand-signaling axis consisting of chemokine receptor CCR7 and its ligands CCL19 and CCL21. The CCL19/CCL21/CCR7 axis enhances the IFN-γ/CXCL9 axis. CXCL9 recruits chemokine receptors CXCR3 in cytotoxic CD8+T cells and natural killer cells, thereby increasing the number of tumor-infiltrating effector immune cells.
The SRC-3 KO Tregs showed notable changes in the expression of IFN-γ, Il-10, Il-35, and TGF-β, and membrane checkpoint inhibitors. The elevation of Il-10, Il-35, and TGF-β is expected to increase/stabilize the number of SRC-3 KO Treg cells in the spleen via autocrine signaling pathways. That then support their later infiltration into tumors, leading to tumor elimination.
These findings suggest that the deletion of SRC-3 changed the expression of a variety of key genes involved in efferent and afferent Treg signaling. The significance of SRC-3 as a pleiotropic regulator of numerous mammalian genes supports this hypothesis.
Importantly, SRC-3 KO Tregs still supported immune checkpoint functions in healthy tissues in the animal, avoiding the severe inflammatory consequences associated with complete loss of Tregs.
The researchers concluded that a disruption in the expression of SRC-3 in Tregs led to a “complete lifetime eradication” of tumors in aggressive syngeneic breast cancer mouse models. It appears that SRC-3KO Tregs confer an extremely long-lasting protection against cancer recurrence in mice without an apparent systemic autoimmune pathological phenotype. Given its known pleiotropic regulation of gene expression, it is not surprising that the disruption of the SRC-3 gene results in dramatic changes in the Treg transcriptomic profile, affecting the expression of key cytokines and membrane signaling molecules.
The authors noted that SRC-3 KO Tregs exhibited a significant potential as a therapeutic approach for cancer therapy. Treatment with SRC-3-deleted Tregs could block tumor growth and recurrence without the autoimmune side effects that usually accompany immune checkpoint modulators. Given these characteristics of SRC-3 biology, further studies are needed to examine the widespread transcriptional effects of this key coactivator of Treg function.
This article was published in PNAS.
Han SJ. Steroid receptor coactivator 3 is a key modulator of regulatory T cell–mediated tumor evasion. PNAS 2023 Vol. 120 No. 23 e2221707120 (Open Access) https://doi.org/10.1073/pnas.2221707120