IL-33 May Be First Stand Alone Biomarker of Prostate Cancer Recurrence Interview with:
Iryna Saranchova MD
PhD candidate
Michael Smith Laboratories
Vancouver, BC What is the background for this study?

• The immune system is efficient at identifying and halting the tumour emergence at early stages. However, when metastatic (sufficient to cause death) tumour appears, the immune system is no longer able to recognize the cancer cells and control their growth and spread.
• Recent studies of solid cancers have shown considerable heterogeneity between different tumour types and several lines of evidence suggest that tumours are not only heterogeneous, but they constantly evolve during the disease progression and this often hampers the existing treatment methods.
• It means that it is important to consider each patient’s mutational changes accumulated over time in antecedent primary, metastatic lesions and/or local recurrences. This approach will help to understand the mechanism of tumour development, create a background for specific treatment modality and prevent therapeutic failure with consequent systemic relapse of the disease
• Therefore, in our project we were aiming to find possible immune markers of tumour transition from the primary stage to its metastatic form. For this purpose, we selected a special study model: two pairs of separate mouse tumour cell lines, where metastatic cells arose from the initial primary tumour. What are the main findings?

• Aiming to find markers of metastatic progression, we conducted a comparative microarray profiling on our study model (antecedent non-metastatic and metastatic cell lines). For our study we selected genes that are involved in novel aspects of inflammation and immunity. Interleukin-33 (IL-33) was one of them.
• First of all, in vivo study, we showed the importance of IL-33 in tumour immunology, while describing a new mechanism that explains how metastatic tumours can outsmart the immune system. Moreover, we have begun to reverse this process, so tumours are revealed to the immune system once again.
• In particular, we show that tumour cells genetically change and evolve during cancer development. As the cells evolve, they lose the ability to create a protein known as IL-33. This protein influences another protein complex, known as the major histocompatibility complex (MHC), which is a carrier of a warning flag on the surface of a primary tumour cell that help identify whether a given cell is a good cell or a bad cell. With IL-33 proteins working, the primary tumour cells put warning flags on the outside of the cell, so that immune cells recognize it and destroy it. When IL-33 disappears, the flag-displaying pathway falls apart and body immune system has no way to recognize and control the cancer cells. We proved that the correlation between IL-33 and MHC-I does exist in human, using RNA-sequencing data collected from resected prostate tumours at Vancouver Prostate Centre (VPC).
• Second, and the most significant, we show that IL-33 is important for cancer medicine, because it is the first stand alone immune biomarker for human prostate cancer.
• With our collaborators at VPC, we analyzed over 300 cases of human prostate tumour samples, and discovered that patients, whose tumours have lost IL-33, have a 5 year more rapid reoccurrence of the disease. To confirm this clinical association, we used publically available data: a similar trend was found in 131 patients with prostate cancer and 513 patients with kidney renal clear cell carcinoma. What should readers take away from your report?

• IL-33 now becomes the first stand alone immune biomarker for Prostate cancer, as it is a bellwether for cancer reoccurrence. Therefore, it will help to predict the prognosis of the disease outcome and optimize treatment plan accordingly. What recommendations do you have for future research as a result of this study?

• To prove that IL-33 down-regulation is a common thread in other carcinomas, the future studies will be conducted using sources from Canadian National Tumour Tissue Bank.
• To study each patient’s mutational landscape accumulated over time in the same patient’s primary, metastatic lesions and/or local recurrences. This sort of personalized treatment approach could identify the exclusive tumour targets of a particular patient and optimize the treatment plan. Is there anything else you would like to add?

• IL-33-protein-complementation treatment can be developed in combination with other anti-cancer therapeutic approaches, such as combination with immune checkpoint blockade therapies (anti-PD-1 or anti-CTLA-4), radio- and chemotherapies to enhance the outcomes. Thank you for your contribution to the community.


Iryna Saranchova, Jeffrey Han, Hui Huang, Franz Fenninger, Kyung Bok Choi, Lonna Munro, Cheryl Pfeifer, Ian Welch, Alexander W. Wyatt, Ladan Fazli, Martin E. Gleave, Wilfred A. Jefferies. Discovery of a Metastatic Immune Escape Mechanism Initiated by the Loss of Expression of the Tumour Biomarker Interleukin-33. Scientific Reports, 2016; 6: 30555 DOI: 10.1038/srep30555

Note: Content is Not intended as medical advice. Please consult your health care provider regarding your specific medical condition and questions.

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Last Updated on September 27, 2016 by Marie Benz MD FAAD