The link between estrogens 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 estrogens are a likely driver of the differences in outcomes.
The researchers reported their findings in a study appearing Oct. 12 in the Journal of Clinical Investigation.
"What we have learned is that immune cells, not cancer cells themselves, are the target of estrogen," 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 tumors are wounds in the process of repair, so the immune system leaves them alone," McDonnell said. "Estrogen 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, Ph.D., a post-doctoral fellow at Duke - describe how estrogens 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 tumor environment, they promote tumor 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 tumor.
The research team tested their findings in wide range of animal models using the drug fulvestrant, an approved drug to block estrogen action. They found that fulvestrant reversed estrogen-enhanced melanoma tumor 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 estrogen 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 tumor 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 estrogen 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 estrogen action in melanoma tumors improves the activity of immunotherapies. Tumors 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."
Donald McDonnell, Ph.D., Senior Author
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.
Chakraborty, B., et al. (2021) Inhibition of estrogen signaling in myeloid cells increases tumor immunity in melanoma. Journal of Clinical Investigation. doi.org/10.1172/JCI151347.