Vancouver, BC – When a person suffers a cut or wound, their immune system leaps into action to prevent infection. After invading pathogens are destroyed, “immune suppressive cells” shut down the body’s immune response so that healthy tissues are not attacked. These cells are a vital part of the wound healing process, but new research by MSFHR Scholar Kevin Bennewith suggests they also serve a more harmful purpose.
Bennewith and colleagues at the BC Cancer Research Centre have assembled a growing body of evidence that immune suppressive cells help to create ideal conditions for the formation of metastatic tumours. When immune suppressive cells accumulate in the lungs, liver, and brain, they create an environment in which the immune system is no longer capable of detecting and destroying metastatic cancer cells. Immune suppressive cells therefore create areas in tissues that help metastatic cancer cells to survive and grow into life-threatening tumour metastases.
Bennewith’s research is looking specifically at breast cancer metastases that form in the lungs to understand the types of immune cells that are involved. In a series of recent publications (below), his team identifies a range of immune suppressive cells – myeloid-derived suppressor cells, macrophages, and regulatory T cells – that play a role in the development of metastatic breast cancer.
This research is crucially important in opening new treatment possibilities for individuals with metastatic cancer.
“Metastases can be very difficult to treat. A lot of cancer patients die from metastatic disease, and we need to improve our understanding of the metastatic process in order to improve therapeutic responses,” said Bennewith.
One of the team’s studies discovered that maraviroc, a drug previously approved for treatment of people infected with HIV, is effective at reducing metastatic tumour growth by blocking one of the receptors that regulatory T cells use to accumulate in tissues and organs. Regulatory T cells are essential for preventing autoimmune disorders in which the immune system attacks itself, and this approach has the benefit of impairing the cells’ ability to accumulate in the lungs while maintaining their normal function.
“We’re excited about the possibilities, because this is an FDA-approved, clinically prescribed drug that we’ve found, at least in our pre-clinical models, can reduce metastasis,” said Bennewith.
The team is also working to improve cancer diagnoses based on the circulation of immune suppressive cells in the bloodstream. Bennewith envisions the possibility of a blood test that could one day help physicians assess patients for their risk of metastases based on the presence or absence of these cells.
Another project in collaboration with MSFHR Scholar Will Lockwood involves modelling the progression of lung cancer to study immune-cell responses as tumours grow. The goals of this work are to develop new diagnostic tests to identify individuals that are likely to develop lung cancer, and to develop therapies that can prevent the accumulation of immune suppressive cells in the lungs of lung cancer patients.
Bennewith credits the support of his 2011 MSFHR Scholar Award as a key factor in advancing his research. “It has been absolutely essential to allow me to develop my research program,” he said. “Without the MSFHR funding, my laboratory would not exist and none of these discoveries would have been made.”
Hamilton MJ, Bosiljcic M, LePard NE, Halvorsen EC, Ho VW, Banath JP, Krystal G and Bennewith KL. J Immunol 192(1): 512-22, 2014.
Halvorsen EC, Mahmoud SM and Bennewith KL. Emerging roles of regulatory T cells in tumour progression and metastasis. Cancer Metastasis Rev 33(4): 1025-41, 2014.
Hamilton MJ, Halvorsen EC, LePard NE, Bosiljcic M, Ho V, Lam V, Banáth JP, Bennewith* KL and Krystal* G. SHIP represses lung inflammation and inhibits mammary tumor metastasis in BALB/c mice. [*Co-senior author] Oncotarget 7(4): 3677-91, 2015.
Conway EM, Pikor LA, Kung S, Hamilton MJ, Lam S, Lam* WL and Bennewith* KL. Macrophages, inflammation, and lung cancer. [*Co-senior author] Am J Resp Crit Care 193(2): 116-30, 2016.
Halvorsen EC, Hamilton MJ, Young A, Wadsworth BJ, LePard NE, Lee HN, Firmino N, Collier JC and Bennewith KL. Maraviroc decreases CCL8-mediated migration of CCR5+ regulatory T cells and reduces metastatic tumour growth in the lungs. Oncoimmunology (Epub ahead of print), 2016.
Krystal G, Hamilton MJ and Bennewith KL. SHIP inhibits metastasis. Aging (Epub ahead of print), 2016.