Steroid Receptor Coactivator 3 Is a Key Modulator of Regulatory T Cell-Mediated Tumor Evasion

Authors

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

Publication Date

6-6-2023

Journal

Proceedings of the National Academy of Sciences of the United States of America

DOI

10.1073/pnas.2221707120

PMID

37253006

PMCID

PMC10266015

PubMedCentral® Posted Date

5-30-2023

PubMedCentral® Full Text Version

Post-Print

Published Open-Access

yes

Keywords

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

Abstract

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.

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