期刊
EMBO REPORTS
卷 21, 期 6, 页码 -出版社
WILEY
DOI: 10.15252/embr.202050162
关键词
bone metastasis; dormancy; immune evasion; prostate cancer; type I interferon
资金
- Prostate Cancer Foundation of Australia
- Movember (Movember Revolutionary Team Award)
- Australian Research Council Future Fellowship [FT130100671]
- Victorian Cancer Agency Mid-career fellowship [MCRF16022]
- Australian Research Council [FT130100671] Funding Source: Australian Research Council
The latency associated with bone metastasis emergence in castrate-resistant prostate cancer is attributed to dormancy, a state in which cancer cells persist prior to overt lesion formation. Using single-cell transcriptomics and ex vivo profiling, we have uncovered the critical role of tumor-intrinsic immune signaling in the retention of cancer cell dormancy. We demonstrate that loss of tumor-intrinsic type I IFN occurs in proliferating prostate cancer cells in bone. This loss suppresses tumor immunogenicity and therapeutic response and promotes bone cell activation to drive cancer progression. Restoration of tumor-intrinsic IFN signaling by HDAC inhibition increased tumor cell visibility, promoted long-term antitumor immunity, and blocked cancer growth in bone. Key findings were validated in patients, including loss of tumor-intrinsic IFN signaling and immunogenicity in bone metastases compared to primary tumors. Data herein provide a rationale as to why current immunotherapeutics fail in bone-metastatic prostate cancer, and provide a new therapeutic strategy to overcome the inefficacy of immune-based therapies in solid cancers.
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