Microbiology & Immunology - Research Publications

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Author: Brockwell, Natasha × Author: Corcoran, Niall × End date: 2022 × Start date: 2020 × Type: Journal Article ×

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    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, C-L ; Pasam, A ; Lyons, RJ ; Duivenvoorden, HM ; Ryan, A ; Butler, LM ; Mariadason, JM ; Phan, TG ; Hayes, VM ; Sandhu, S ; Swarbrick, A ; Corcoran, NM ; Hertzog, PJ ; Croucher, P ; Hovens, C ; Parker, BS (WILEY, 2020-06-04)
    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.