Metastatic Tumor Cells Evade Immune Recognition by IL-33 Downregulation

Cancer is one of the leading causes of morbidity and mortality worldwide, with cancer-related deaths totaling 8.2 million in 2012. In addition, diagnosed cases of cancer are expected to increase from 14.1 million to 22 million new cases annually in the next two decades. The development of cancer is believed to involve a combination of factors, including gene mutations in oncogenes and tumor suppressor genes. These mutations allow for abnormal proliferation of cells and the development of tumors. The most lethal form of cancer occurs when tumor cells are able to travel to distant sites in the body, known as metastasis. The complex processes of metastasis are not fully understood, but research has identified a “metastatic gene signature” that differentiates tumor cells that grow locally from those that can metastasize. One component of the metastatic gene signature is immune evasion, and the ability of tumor cells to go undetected by the immune system. Researchers at the University of British Columbia sought to further understand the method by which tumor cells evade the immune system. Their findings were recently published in Scientific Reports.

Immune Surveillance and Cancer

One of the primary functions of the immune system is to identify and dispose of abnormal or infected cells. Tumor cells presenting tumor cell peptides on cell surface MHC-1 can be recognized by CD8+ T cells and targeted for destruction. Additionally, tumor cell growth is influenced by the local microenvironment and interactions with other cells in the tissue, including immune cells that interact through direct contact and through cytokine-related signaling pathways. The cytokine IL-33 is a pro-inflammatory cytokine with confounding research indicating it can be both immunoprotective and promote tumor growth. Dr. Wilfred Jefferies and colleagues at the University of British Columbia examined the role of IL-33 in tumorigenesis in models of lung and prostate cancers.

IL-33 Protects Against Tumor Growth and Metastasis

Jefferies and colleagues first examined the expression of IL-33 in benign tumors, primary tumors and metastatic tumors and found IL-33 expression to be downregulated in metastatic tumors. MHC-1 is responsible for helping immune cells recognize tumor cells, and downregulation of MHC-1 has been demonstrated to be a key factor in tumor growth and metastasis. To determine the effects of IL-33 expression on MHC-1 expression, IL-33 was downregulated and upregulated in primary tumor cells. Downregulation of IL-33 resulted in decreased MHC-1 expression. Conversely, upregulation of IL-33 resulted in increased MHC-1 expression. These findings suggest that IL-33 is important in regulating immune-recognizable tumors. Furthermore, mice with tumors expressing IL-33 displayed reduced tumor growth and a decrease in circulating tumor cells compared to controls. The researchers then examined the effect of IL-33 expression on tumor-infiltrating immune cells and found that IL-33 expressing tumors had higher levels of immune cells and a reduction in immune suppressive cells.

This study indicates a critical role of IL-33 in regulating metastasis, tumor growth and immune recognition in cancer. Further, this study describes a novel strategy by tumor cells to evade the immune system by downregulating IL-33 expression during the transition from primary tumors to metastatic tumors. Consequently, IL-33 may be a useful target for generalized cancer therapies in metastatic disease.

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