Steroid receptor coactivator 3 is a key modulator of regulatory T cell–mediated tumor evasion

Sang Jun Han, Prashi Jain, Yosef Gilad, Yan Xia, Nuri Sung, Mi Jin Park, Adam M. Dean, Rainer B. Lanz, Jianming Xu, Clifford C. Dacso, David M. Lonard, Bert W. O'Malley

Research output: Contribution to journalArticlepeer-review

2 Scopus citations


Steroid receptor coactivator 3 (SRC-3) is most strongly expressed in regulatory T cells (Tregs) and B cells, suggesting that it plays an important role in the regulation of Treg function. Using an aggressive E0771 mouse breast cell line syngeneic immune-intact murine model, we observed that breast tumors were “permanently eradicated” in a genetically engineered tamoxifen-inducible Treg-cell-specific SRC-3 knockout (KO) female mouse that does not possess a systemic autoimmune pathological phenotype. A similar eradication of tumor was noted in a syngeneic model of prostate cancer. A subsequent injection of additional E0771 cancer cells into these mice showed continued resistance to tumor development without the need for tamoxifen induction to produce additional SRC-3 KO Tregs. SRC-3 KO Tregs were highly proliferative and preferentially infiltrated into breast tumors by activating the chemokine (C-C motif) ligand (Ccl) 19/Ccl21/ chemokine (C-C motif) receptor (Ccr)7 signaling axis, generating antitumor immunity by enhancing the interferon-γ/C-X-C motif chemokine ligand (Cxcl) 9 signaling axis to facilitate the entrance and function of effector T cells and natural killer cells. SRC-3 KO Tregs also show a dominant effect by blocking the immune suppressive function of WT Tregs. Importantly, a single adoptive transfer of SRC-3 KO Tregs into wild-type E0771 tumor-bearing mice can completely abolish preestablished breast tumors by generating potent antitumor immunity with a durable effect that prevents tumor reoccurrence. Therefore, treatment with SRC-3-deleted Tregs represents an approach to completely block tumor growth and recurrence without the autoimmune side effects that typically accompany immune checkpoint modulators.

Original languageEnglish (US)
Article numbere2221707120
Pages (from-to)e2221707120
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number23
StatePublished - Jun 6 2023


  • adoptive cell transfer
  • interferon-γ
  • regulatory T cells
  • steroid receptor coactivator 3
  • syngeneic murine model of breast cancer
  • Humans
  • Male
  • Breast Neoplasms
  • Mice, Knockout
  • Animals
  • Nuclear Receptor Coactivator 3/genetics
  • T-Lymphocytes, Regulatory
  • Female
  • Ligands
  • Mice
  • Mammary Neoplasms, Animal
  • Tamoxifen/pharmacology

ASJC Scopus subject areas

  • General


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