2. Academic Validation
  3. Astrocyte-induced Cdk5 expedites breast cancer brain metastasis by suppressing MHC-I expression to evade immune recognition

Astrocyte-induced Cdk5 expedites breast cancer brain metastasis by suppressing MHC-I expression to evade immune recognition

  • Nat Cell Biol. 2024 Oct;26(10):1773-1789. doi: 10.1038/s41556-024-01509-5.
Arseniy E Yuzhalin 1,  Frank J Lowery 1 2,  Yohei Saito 1,  Xiangliang Yuan 1,  Jun Yao 1,  Yimin Duan 1,  Jingzhen Ding 1,  Sunil Acharya 1,  Chenyu Zhang 1,  Abigail Fajardo 1,  Hao-Nien Chen 1,  Yongkun Wei 1,  Yutong Sun 1,  Lin Zhang 1,  Yi Xiao 1,  Ping Li 1,  Philip L Lorenzi 3,  Jason T Huse 4,  Huihui Fan 5 6,  Zhongming Zhao 5,  Mien-Chie Hung 1 7,  Dihua Yu 8
Affiliations

Affiliations

  • 1 Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • 2 Surgery Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
  • 3 Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • 4 Departments of Pathology and Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • 5 Center for Precision Health, McWilliams School of Biomedical Informatics, Houston, TX, USA.
  • 6 John P and Katherine G McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, USA.
  • 7 Graduate Institute of Biomedical Sciences, Research Center for Cancer Biology and Center for Molecular Medicine, China Medical University, Taichung City, Taiwan.
  • 8 Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. dyu@mdanderson.org.
PMID: 39304713 DOI: 10.1038/s41556-024-01509-5
Abstract

Brain metastases (BrMs) evade the immune response to develop in the brain, yet the mechanisms of BrM immune evasion remains unclear. This study shows that brain astrocytes induce the overexpression of neuronal-specific cyclin-dependent kinase 5 (CDK5) in breast cancer-derived BrMs, which facilitates BrM outgrowth in mice. Cdk5-overexpressing BrMs exhibit reduced expression and function of the class I major histocompatibility complex (MHC-I) and antigen-presentation pathway, which are restored by inhibiting CDK5 genetically or pharmacologically, as evidenced by single-cell RNA Sequencing and functional studies. Mechanistically, CDK5 suppresses MHC-I expression on the Cancer cell membrane through the Irf2bp1-Stat1-importin α-Nlrc5 pathway, enabling BrMs to avoid recognition by T cells. Treatment with roscovitine-a clinically applicable CDK5 inhibitor-alone or combined with Immune Checkpoint inhibitors, significantly reduces BrM burden and increases tumour-infiltrating functional CD8+ lymphocytes in mice. Thus, astrocyte-induced CDK5 overexpression endorses BrM immune evasion, whereas therapeutically targeting CDK5 markedly improves the efficacy of Immune Checkpoint inhibitors and inhibits BrM growth.

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