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

Owen, KL; Gearing, LJ; Zanker, DJ; Brockwell, NK; Khoo, WH; Roden, DL; Cmero, M; Mangiola, S; Hong, MK; Spurling, AJ; McDonald, M; Chan, CL; Pasam, A; Lyons, RJ; Duivenvoorden, HM; Ryan, A; Butler, LM; Mariadason, JM; Giang Phan, T; Hayes, VM; Sandhu, S; Swarbrick, A; Corcoran, NM; Hertzog, PJ; Croucher, PI; Hovens, C; Parker, BS

Author(s): Owen, KL; Gearing, LJ; Zanker, DJ; Brockwell, NK; Khoo, WH; Roden, DL; Cmero, M; Mangiola, S; Hong, MK; Spurling, AJ; McDonald, M; Chan, CL; Pasam, A; Lyons, RJ; Duivenvoorden, HM; Ryan, A; Butler, LM; Mariadason, JM; Giang Phan, T; Hayes, VM; Sandhu, S; Swarbrick, A; Corcoran, NM; Hertzog, PJ; Croucher, PI; Hovens, C; Parker, BS;
Details: Publication Year 2020-06-04,Volume 21,Issue #6,Page e50162
Journal Title: EMBO Reports
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.
Publisher: Embo Press
Keywords: *bone metastasis; *dormancy; *immune evasion; *prostate cancer; *type I interferon;
Research Division(s): Bioinformatics
Publisher's Version: https://doi.org/10.15252/embr.202050162
Open Access at Publisher's Site: https://doi.org/10.15252/embr.202050162
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2021-03-04 09:47:04

Last Modified: 2021-03-08 11:21:00