What is it about?
Regulatory T (Treg) cells play a crucial role in maintaining immune homeostasis by restraining immune responses. Tregs can foster a tumor-promoting immune microenvironment during cancer progression by suppressing cytotoxic immune cells, such as T-lymphocytes. The Steroid Receptor Coactivator (SRC)-3, the second most highly expressed transcriptional coactivator in Tregs, is implicated in Treg function. Deletion of the SRC-3 gene only in Tregs leads to "complete lifetime eradication" of tumors in aggressive breast and prostate cancer mouse models. This is because the deletion of SRC-3 modifies the expression of a broad range of crucial genes involved in both efferent and afferent Treg signaling. Tregs with SRC-3 gene knocked-out (SRC-3KO) offer long-lasting protection against cancer recurrence in mice without inducing adverse toxic effects, such as cytokine storms. Furthermore, one injection of SRC-3 KO Tregs into tumor-bearing mice leads to complete tumor eradication without subsequent cancer recurrence. Therefore, utilizing SRC-3-deleted Tregs could be an innovative and practical approach to preventing tumor growth and recurrence.
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Why is it important?
Tregs play a critical role in cancer progression by creating an immune-suppressive tumor microenvironment, making them a significant focus for immune checkpoint inhibitor therapeutic development. While most Treg-based immune checkpoint modulators target cell membrane signaling proteins, systemic injection of antibodies targeting these proteins results in toxicity, including severe autoinflammation in Treg-targeted cancer immunotherapies involving cytotoxic T-lymphocyte–associated antigen 4 blockades. Moreover, the effectiveness of current immune cell therapies, such as chimeric antigen receptor-T cell therapy, in treating solid tumors has yet to be widely achieved, and significant side effects can limit their use. Since SRC-3 KO Tregs do not produce the strong, generalized autoimmune side effects typically associated with other immune checkpoint inhibitors, the dose of SRC-3 KO Tregs in cell therapy does not seem to be limited by dose-dependent toxicities. SRC-3KO Tregs have shown the ability to provide remarkably long-lasting protection against the progression and recurrence of solid cancers in mice, suggesting that SRC-3 KO Tregs hold promise as a cell-based therapeutic agent for treating various cancers.
Perspectives
The modulation of Tregs through genetic modification of a key coactivator, thereby activating the patient's immune response to cancer, represents a significant and groundbreaking advancement in the battle against this disease. This approach is unparalleled, and the potential implications for achieving a global triumph over cancer are incalculable.
Sang Jun Han
Baylor College of Medicine
Read the Original
This page is a summary of: Steroid receptor coactivator 3 is a key modulator of regulatory T cell–mediated tumor evasion, Proceedings of the National Academy of Sciences, May 2023, Proceedings of the National Academy of Sciences,
DOI: 10.1073/pnas.2221707120.
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