While the role of oestrogen signalling in tumour development is well understood in breast and ovarian cancer, its role in anti-tumour immunity has not been extensively studied.

However, new research from The Wistar Institute showed that oestrogen

These findings pave the way for combining immunotherapeutic treatments with anti-oestrogen drugs that may significantly extend survival. Study results were published in the journal Cancer Discovery.

"We know about oestrogen's effects directly on tumour cells, but the tumour microenvironment plays a critical role in determining malignant progression as well as response to therapy," said José R. Conejo-Garcia, M.D., Ph.D., professor in the Tumour Microenvironment and Metastasis program at The Wistar Institute and lead author of the study. "Both oestrogen receptors are expressed on most immune cells, so we knew there had to be a larger role that oestrogen played in cancer development."

Oestrogen hormones bind to two high-affinity oestrogen receptors (ERα and ERβ), and when a tumour is ER-positive, it could receive signals from oestrogens that promote its growth and enhance its role in malignant progression.

Because of this, ER-positive breast cancer is often treated with anti-oestrogen therapy like tamoxifen, which has been shown to have both positive and negative effects.

While it decreases oestrogen signalling in the tumour, it can increase oestrogen signalling elsewhere in the body.

The same therapeutic strategy has been tested in ovarian cancer, but results showed only mild effectivity with about 31 percent of ovarian cancers being ERα and about 60 percent being ERβ.

Conejo-Garcia and colleagues found that oestrogen signalling is closely linked to both the accumulation and activity of myeloid-derived suppressor cells (MDSCs), a set of immune cells associated with tumours treatment resistance.

Oestrogen enables immunosuppression in a two-pronged approach involving MDSCs.

First, the oestrogen drives the mobilisation of MSDCs.

Then, at the same time, it makes a subset of the MDSCs more immunosuppressive in vivo.

Oestrogen supplementation accelerated the growth of multiple models oestrogen-insensitive tumours in immunocompetent animals, while ablating oestrogen production by resecting the ovaries boosted anti-tumour immunity and delayed malignant progression.

Importantly, differences in tumour progression disappeared in immunodeficient mice, demonstrating that oestrogen-mediated acceleration of tumour growth depends on dampening protective anti-tumour immunity.

They also demonstrated how ERα is responsible for enhancing the activity of multiple pathways that are already associated with cancer development.

This oestrogen receptor activated the STAT3 pathway, which has already been linked to cancer cell survival and the expansion of MDSCs in cancer-bearing hosts.

It was also able to activate this pathway by enhancing the activity of JAK2 and SRC, two proteins linked to cancer development and immune response.

These cancer pathways are activated in a variety of inflammatory cancers in non-tumour cells, such as breast cancer, ovarian cancer, and melanoma.

Since oestrogen is present not just pre-menopausal women but men and post-menopausal women as well, the authors propose that investigating anti-oestrogen therapeutic strategies could lead to new treatments for a variety of cancers.

This strategy could halt the MDSCs and tumour initiation.

"Oestrogens have a profound effect on anti-tumour immunity and tumour-promoting inflation that is completely independent from their direct activity on tumour cells," Conejo-Garcia added. "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 oestrogen receptors in tumour cells alone."

Source: Cancer Discovery