The link between oestrogens and breast cancer has long been defined, but a Duke-led research team has identified how these hormones can also influence the growth of other cancers, notably melanoma.

Building on observations that male melanoma patients who are treated with immune checkpoint inhibitors tend to have better responses than women, the team found that oestrogens are a likely driver of the differences in outcomes.

The researchers reported their findings in a study appearing in the Journal of Clinical Investigation.

“What we have learned is that immune cells, not cancer cells themselves, are the target of oestrogen,” said senior author Donald McDonnell, Ph.D., a member of the Duke Cancer Institute and professor in the departments of Pharmacology & Cancer Biology and Medicine at Duke University School of Medicine.

“The cancer cells fool the immune system into believing that tumours are wounds in the process of repair, so the immune system leaves them alone,” McDonnell said. “Oestrogen enables this sleight of hand.”

In the study, McDonnell and colleagues from both Duke and the University of North Carolina at Chapel Hill – including lead author Binita Chakraborty, a post-doctoral fellow at Duke – describe how oestrogens modulate immune cell function in melanoma through a type of immune cell called macrophages.

Among other things, macrophages are involved in wound repair, and in the melanoma tumour environment, they promote tumour growth by increasing the blood supply and blocking the activation of another class of immune cells, T cells, that would normally be activated against the tumour.

The research team tested their findings in wide range of animal models using the drug fulvestrant, an approved drug to block oestrogen action. They found that fulvestrant reversed oestrogen-enhanced melanoma tumour growth by activating T cells.

The drug also worked to increase the efficacy of approved immunotherapies, which have greatly improved the outcomes for melanoma patients, but eventually become less effective. Adding an oestrogen suppressing drug might prolong the benefit of immunotherapies.

In collaboration with colleagues in the Duke Cancer Institute’s Center for Immunotherapy McDonnell and his team will test that approach shortly in a clinical trial at Duke. He said their most recent data suggests that a similar approach could be effective in other cancers, including lung and colon cancers.

“It is clear that one of the major ways that cancers evade immunotherapy is the presence of immunosuppressive macrophages in the tumour microenvironment,” said Scott Antonia, M.D., Ph.D., professor of medicine at Duke who is working to launch a clinical trial testing the use of oestrogen suppression drugs in different cancers.

“This novel discovery of a means of reducing the number of these cells in cancer patients will likely be an important strategy to improve the clinical efficacy of immunotherapy in a wide variety of cancers,” Antonia said.

“The bottom line is that restricting oestrogen action in melanoma tumours improves the activity of immunotherapies,” McDonnell said. “Tumours find a way around the immune system – in this case looking like they are involved in wound repair – but now we know this and perhaps there is a way to fight back.”

In additional to McDonnell and Chakraborty, study authors include Jovita Byemerwa, Jonathan Shepherd, Corinne Haines, Robert Baldi, Weida Gong, Wen Liu, Debarati Mukherjee, Sandeep Artham, Felicia Lim, Yeeun Bae, Olivia Brueckner, Kendall Tavares, Suzanne Wardell, Brent Hanks, Charles Perou and Ching-Yi Chang.

The study received funding support from the Melanoma Research Foundation (640233), the Susan G. Komen Foundation (SAC180085, SAC160074), and the Duke Cancer Institute.

Source: Duke Cancer Institute