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Prostate cancer cell‐intrinsic interferon signaling regulates dormancy and metastatic outgrowth in bone
Author(s) -
Owen Katie L,
Gearing Linden J,
Zanker Damien J,
Brockwell Natasha K,
Khoo Weng Hua,
Roden Daniel L,
Cmero Marek,
Mangiola Stefano,
Hong Matthew K,
Spurling Alex J,
McDonald Michelle,
Chan ChiaLing,
Pasam Anupama,
Lyons Ruth J,
Duivenvoorden Hendrika M,
Ryan Andrew,
Butler Lisa M,
Mariadason John M,
Giang Phan Tri,
Hayes Vanessa M,
Sandhu Shahneen,
Swarbrick Alexander,
Corcoran Niall M,
Hertzog Paul J,
Croucher Peter I,
Hovens Chris,
Parker Belinda S
Publication year - 2020
Publication title -
embo reports
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.584
H-Index - 184
eISSN - 1469-3178
pISSN - 1469-221X
DOI - 10.15252/embr.202050162
Subject(s) - dormancy , interferon , cancer research , prostate cancer , biology , signal transduction , microbiology and biotechnology , cancer , immunology , genetics , botany , germination
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.