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 the Journal of Clinical Investigation. Senior author Donald McDonnell, PhD, a member of the Duke Cancer Institute and professor in the departments of Pharmacology & Cancer Biology and Medicine at Duke University, explain the concept: “What we have learned is that immune cells, not cancer cells themselves, are the target of estrogen. 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. Estrogen enables this sleight of hand.”
The classification of melanoma as a hormone-sensitive neoplasm is still controversial, because most of the research ha been focused on reproductive cancers. This is why the importance of hormone associated risk factors, such as pregnancy, menopausal status, hormone therapies and the use of oral contraceptives, on the pathobiology of this disease must be deepen. While the potential effects of sex steroids on melanoma risk needs to be assessed in large clinical studies, there are already evidences that the incidence of secondary melanoma is significantly lower in anti-estrogen treated breast cancer patients than in the general population. Beside mediateing their physiological actions in cells through the classical nuclear receptors, estrogens may use the membrane G-protein coupled receptor GPER1 (also GPR30) to stimulate cells. A recent study by Natale et al highlighted a tumor cell-intrinsic role for GPER1 in regulating melanocyte differentiation, thereby preventing melanoma cell proliferation.
In their research, McDonnell and colleagues 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 T lymphocytes. The research team tested their findings in wide range of animal models using the drug fulvestrant, an approved estrogen antagonist. 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 over time. Adding an anti-estrogen might prolong the benefit of immunotherapies. In collaboration with colleagues in the Duke Cancer Institute’s Center for Immunotherapy, the team will test that approach shortly in a clinical trial.
Senior leader Scott Antonia, MD, PhD, professor of Medicine at Duke who is working to launch a clinical trial testing the use of estrogen suppression drugs in different cancers, commented: “It is clear that one of the major ways that cancers evade immunotherapy is the presence of immunosuppressive macrophages in the tumor microenvironment. 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. Most recent data suggests that a similar approach could be effective in other cancers, including lung and colon cancers. 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.”
- Edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.
Chakraborty B et a. J Clin Invest. 2021 Oct 12:e151347.
Bhari N, Schwaertz R et al. J Cosmet Dermatol. 2021 Aug 20.
Sun Q et al. Clin Epidemiol. 2020 Oct 29; 12:1183-1203.
Natale CA, Li J, Zhang J et al. Elife. 2018 Jan 16; 7:e31770.
Dott. Gianfrancesco Cormaci
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