NR1D1 Stimulates Antitumor Immune Responses in Breast Cancer by Activating cGAS-STING Signaling.

Abstract

Potentiating antitumor immunity is a promising therapeutic approach for treating a variety of cancers, including breast cancer. One potential strategy to promote antitumor immunity is targeting DNA damage response. Given that the nuclear receptor NR1D1 (also known as REV-ERBα) inhibits DNA repair in breast cancer cells, we explored the role of NR1D1 in antitumor CD8+ T-cell responses. First, deletion of Nr1d1 in MMTV-PyMT transgenic mice resulted in increased tumor growth and lung metastasis. Orthotopic allograft experiments suggested that loss of Nr1d1 in tumor cells rather than in stromal cells played a prominent role in increasing tumor progression. Comprehensive transcriptome analyses revealed that biological processes including type I IFN signaling and T cell-mediated immune responses were associated with NR1D1. Indeed, the expression of type I IFNs and infiltration of CD8+ T cells and natural killer cells in tumors were suppressed in Nr1d1-/-;MMTV-PyMT mice. Mechanistically, NR1D1 promoted DNA damage-induced accumulation of cytosolic DNA fragments and activated cGAS-STING signaling, which increased the production of type I IFNs and downstream chemokines CCL5 and CXCL10. Pharmacologic activation of NR1D1 by its ligand, SR9009, enhanced type I IFN-mediated antitumor immunity accompanied by the suppression of tumor progression and lung metastasis. Taken together, these findings reveal the critical role of NR1D1 in enhancing antitumor CD8+ T-cell responses, suggesting that NR1D1 may be a good therapeutic target for breast cancer.

SIGNIFICANCE:

NR1D1 suppresses breast cancer progression and lung metastasis by enhancing antitumor immunity via cGAS-STING pathway activation, which provides potential immunotherapeutic strategies for breast cancer.

• Authors: Na-Lee Ka, Mi Kyung Park, Seung-Su Kim, Yoon Jeon, Sewon Hwang, Sun Mi Kim, Ga Young Lim, Ho Lee, Mi-Ock Lee
• Journal: Cancer research (Cancer Res) Vol. 83 Issue 18 Pg. 3045-3058 (09 15 2023) ISSN: 1538-7445 [Electronic] United States
• PMID: 37395684 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: ©2023 The Authors; Published by the American Association for Cancer Research.

Chemical References

• Interferon Type I
• Nucleotidyltransferases
• Nr1d1 protein, mouse

Topics

• Animals
• Mice
• DNA Repair
• Immunity
• Interferon Type I (metabolism)
• Lung Neoplasms (pathology)
• Nucleotidyltransferases (genetics)
• Signal Transduction