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Type: Journal article
Title: Prostate cancer cell-intrinsic interferon signaling regulates dormancy and metastatic outgrowth in bone
Author: Owen, K.L.
Gearing, L.J.
Zanker, D.J.
Brockwell, N.K.
Khoo, W.H.
Roden, D.L.
Cmero, M.
Mangiola, S.
Hong, M.K.
Spurling, A.J.
McDonald, M.
Chan, C.-.L.
Pasam, A.
Lyons, R.J.
Duivenvoorden, H.M.
Ryan, A.
Butler, L.M.
Mariadason, J.M.
Phan, T.G.
Hayes, V.M.
et al.
Citation: EMBO Reports, 2020; 21(6):e50162-1-e50162-24
Publisher: EMBO Press
Issue Date: 2020
ISSN: 1469-221X
Statement of
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 Duivenvoorden, Andrew Ryan, Lisa M Butler, John M Mariadason, Tri Giang Phan, Vanessa M Hayes, Shahneen Sandhu, Alexander Swarbrick, Niall M Corcoran, Paul J Hertzog, Peter I Croucher, Chris Hovens, Belinda S Parker
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.
Keywords: Bone metastasis; dormancy; immune evasion; prostate cancer; type I interferon
Rights: © 2020 Peter MacCallum Cancer Centre. Published under the terms of the CC BY NC ND 4.0 license This is an open access article under the terms of the Creative Commons Attribution- NonCommercial-NoDerivs 4.0 License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.
RMID: 1000022966
DOI: 10.15252/embr.202050162
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