Oral Presentation The Melbourne Immunotherapy Network Winter Symposium 2019

Utilizing tumor-intrinsic IFN signaling to predict and prevent prostate cancer progression in bone (#5)

Katie Owen 1 2 , Jamie Gearing 3 4 , Damien Zanker 1 2 , Natasha Brockwell 1 2 , Marek Cmero 5 , Weng Hua Khoo 6 , Alex Spurling 1 2 , Alexander Swarbrick 6 7 , Peter Croucher 7 , Niall Corcoran 8 9 , Paul Hertzog 3 4 , Chris Hovens 8 9 , Belinda Parker 1 2
  1. La Trobe Institute for Molecular Science, Department of Biochemistry and Genetics, La Trobe University, Melbourne, VIC, Australia
  2. 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. Department of Computing and Information Systems, University of Melbourne, Parkville , VIC, Australia
  6. Cancer Research Division, The Kinghorn Cancer Centre, Sydney, NSW, Australia
  7. Garvan Institute of Medical Research, Sydney, NSW, Australia
  8. Departments of Urology and Surgery, Royal Melbourne Hospital and The University of Melbourne, Parkville , VIC, a
  9. Australian Prostate Cancer Research Centre Epworth, Richmond, VIC, Australia

Bone metastasis is a fatal consequence of prostate cancer that can occur many years after initial primary diagnosis. This latency associated with delayed emergence in bone-avid solid cancers is linked to dormancy, which restricts outgrowth yet facilitates tumor cell persistence. Immune regulation of dormancy has long-been been proposed. However, direct evidence to support this as a mechanism of induction and outgrowth in the osteoimmune milieu is lacking.

Utilizing a membrane-labeling and single cell sequencing approach, we have recently interrogated the transcriptomes of dormant and proliferating cells in bone. Our findings demonstrated that over 55% of genes lost in actively proliferating cells were interferon (IFN) regulated genes (IRGs), primarily those involved in tumor-inherent immunogenicity and immune modulation. We further demonstrated that loss of IFN pathways in active prostate cancer cells is bone-specific and inducible by a subset of immunosuppressive cells concentrated in the bone-tumor microenvironment that have been linked to metastatic progression. Moreover, we confirmed loss of IRG signatures in bone metastases of prostate cancer patients. In fact, loss of core IRGs in primary tumors was associated with rapid metastasis in a large prostate cancer cohort. Additionally, we identified core IFN-associated biomarkers of skeletal modulatory processes that robustly predict biochemical recurrence in patients with early disease. Importantly, our studies have shown that accelerated metastasis to bone as a result of tumor-intrinsic IFN loss can be abrogated through epigenetic targeting and immunotherapeutic intervention, inducing IFN-dependent T cell memory responses and innate immune activation.

These findings suggest downregulation of tumour-intrinsic IFN signalling is a critical driver of prostate cancer outgrowth in bone, and that this loss promotes tumour progression by engendering a permissive osteoimmune niche, including the induction of errant bone-remodelling. This work demonstrates the potential of therapeutic intervention to treat/prevent bone metastasis in prostate cancer, with the aim of reducing patient mortality.