Estrogen signaling cuts immune response in cancers other than breast, ovarian

The Wistar Institute--Courtesy of Jeffrey M. Vinocur CC BY-SA 3.0

Wistar Institute scientists have found that, in addition to driving breast and ovarian cancer growth, the hormone estrogen plays a role in tamping down the immune response against various cancers. The findings, reported in the journal Cancer Discovery, could result in new combination therapies involving antiestrogen drugs that could increase cancer survival rates.

"Estrogens have a profound effect on anti-tumor immunity and tumor-promoting inflation that is completely independent from their direct activity on tumor cells," said Dr. José Conejo-Garcia, a professor in the Tumor Microenvironment and Metastasis program at The Wistar Institute and lead author of the study, in a statement. "With the continued development of emerging immunotherapies to treat cancer, we believe that combination strategies could significantly extend the survival of cancer patients independently of estrogen receptors in tumor cells alone."

The relationship between estrogen and tumor cells is straightforward: if it has estrogen receptors, a tumor cell may receive signals from the hormone that boost its growth, according to the statement. This is why some estrogen receptor-positive breast cancers are treated with antiestrogen meds. But the Wistar team found that estrogen has a deeper relationship with the tumor microenvironment, namely the environment in which the tumor exists, including blood vessels, signaling molecules and immune cells.

"We know about estrogen's effects directly on tumor cells, but the tumor microenvironment plays a critical role in determining malignant progression as well as response to therapy," said Conejo-Garcia in the statement. "Both estrogen receptors are expressed on most immune cells, so we knew there had to be a larger role that estrogen played in cancer development."

Conejo-Garcia’s team found that estrogen signaling has two effects on myeloid-derived suppressor cells (MDSCs), which are a type of immune cell linked with treatment resistance in tumors, according to the statement. Estrogen promotes the mobilization of these cells, causing them to accumulate, and it also spurs the immunosuppressive action of certain MDSCs. In the study, the researchers found that giving estrogen to mice with normal immune responses upped the growth of estrogen-insensitive tumors. They also found that removing the ovaries--and thus estrogen production--from mice boosted the antitumor immune response and blocked malignant progression.

Since men and postmenopausal women produce estrogen as well as premenopausal women, the potential applications of an immunotherapeutic-antiestrogen-drug combo would be far-ranging. Wistar’s business development team is on the hunt for a licensing partner to help develop antiestrogen therapeutics for various cancers that are not traditionally associated with this kind of therapy.