Prostate cancer cell-intrinsic interferon signaling regulates dormancy and metastatic outgrowth in bone

Katie L. Owen, Linden J. Gearing, Damien J. Zanker, Natasha K. Brockwell, Weng Hua Khoo, Daniel L. Roden, Marek Cmero, Stefano Mangiola, Matthew K. Hong, Alex J. Spurling, Michelle McDonald, Chia-Ling Chan, Anupama Pasam, Ruth J. Lyons, Hendrika M. Duivenoorden, Andrew Ryan, Lisa M. Butler, John M. Mariadason, Tri Giang Phan, Vanessa M. HayesShahneen Sandhu, Alexander Swarbrick, Niall M. Corcoran, Paul J. Hertzog, Peter I. Croucher, Christopher Hovens, Belinda S. Parker

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Abstract

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.
Original languageEnglish
Article numbere50162
Number of pages24
JournalEMBO REPORTS
Volume21
Issue number6
Early online date21 Apr 2020
DOIs
Publication statusPublished - 4 Jun 2020
Externally publishedYes

Keywords

  • bone metastasis
  • dormancy
  • immune evasion
  • prostate cancer
  • type I interferon

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