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 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

doi:10.15252/embr.202050162

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

EMBO Rep. 2020 Jun 4;21(6):e50162. doi: 10.15252/embr.202050162. Epub 2020 Apr 21.

Authors

Katie L Owen^{1

2}, Linden J Gearing^{3

4}, Damien J Zanker^{1

2}, Natasha K Brockwell^{1

2}, Weng Hua Khoo^{5

6}, Daniel L Roden^{7

8}, Marek Cmero⁹, Stefano Mangiola¹⁰, Matthew K Hong^{11

12}, Alex J Spurling¹, Michelle McDonald⁷, Chia-Ling Chan⁶, Anupama Pasam¹³, Ruth J Lyons¹⁴, Hendrika M Duivenvoorden¹, Andrew Ryan¹⁵, Lisa M Butler^{16

17}, John M Mariadason¹⁸, Tri Giang Phan^{6

19}, Vanessa M Hayes^{6

14}, Shahneen Sandhu²⁰, Alexander Swarbrick^{5

6}, Niall M Corcoran^{11

21

22}, Paul J Hertzog^{3

4}, Peter I Croucher^{6

7

8}, Chris Hovens^{11

12}, Belinda S Parker^{1

2

23}

Affiliations

¹ La Trobe Institute for Molecular Science, Department of Biochemistry and Genetics, La Trobe University, Melbourne, Vic., Australia.
² Cancer Immunology and Therapeutics Programs, Peter MacCallum Cancer Centre, Melbourne, Vic., Australia.
³ Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, Vic., Australia.
⁴ Department of Molecular and Translational Science, Monash University, Clayton, Vic., Australia.
⁵ Division of Bone Biology, Garvan Institute of Medical Research, Sydney, NSW, Australia.
⁶ School of Biotechnology and Biomolecular Sciences, UNSW Sydney, Sydney, NSW, Australia.
⁷ Cancer Research Division, The Kinghorn Cancer Centre/Garvan Institute of Medical Research, Sydney, NSW, Australia.
⁸ St Vincent's Clinical School, UNSW Sydney, Sydney, NSW, Australia.
⁹ Murdoch Children's Research Institute, Parkville, Vic., Australia.
¹⁰ Bioinformatics Division, The Walter and Eliza Hall Institute, Parkville, Vic., Australia.
¹¹ Departments of Urology and Surgery, Royal Melbourne Hospital, The University of Melbourne, Parkville, Vic., Australia.
¹² Australian Prostate Cancer Research Centre Epworth, Richmond, Vic., Australia.
¹³ Translational Research Laboratory, Peter MacCallum Cancer Centre, Melbourne, Vic., Australia.
¹⁴ Genomics and Epigenetics Division, Garvan Institute of Medical Research, Sydney, NSW, Australia.
¹⁵ TissuePath Specialist Pathology, Mount Waverley, Vic, Australia.
¹⁶ Freemason's Foundation Centre for Men's Health, University of Adelaide Medical School, Adelaide, SA, Australia.
¹⁷ South Australian Health and Medical Research Institute, Adelaide, SA, Australia.
¹⁸ Olivia Newton-John Cancer Research Institute, Heidelberg, Vic., Australia.
¹⁹ Division of Immunology, Garvan Institute of Medical Research, Sydney, NSW, Australia.
²⁰ Central Clinical School, University of Sydney, Camperdown, NSW, Australia.
²¹ Department of Medical Oncology, Peter MacCallum Cancer Centre, University of Melbourne, Melbourne, Vic., Australia.
²² Department of Urology, Frankston Hospital, Frankston, Vic., Australia.
²³ Sir Peter MacCallum, Department of Oncology, University of Melbourne, Parkville, Vic., Australia.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Bone Neoplasms* / drug therapy
Bone Neoplasms* / genetics
Humans
Interferons
Male
Prostatic Neoplasms* / genetics
Signal Transduction

Substances

Interferons

Abstract

Publication types

MeSH terms

Substances

Grants and funding