1. Galamba, Elizabeth Rose

Article Content

Estrogens are known to influence tumor formation and growth of mammary tumors and other gynecological cancers, but until the completion of a recent study, researchers were unaware of estrogen's effect on other cancer types. However, this study found that estrogens promote the establishment of an environment that supports the growth and protection of melanoma tumors.

melanoma. melanoma... - Click to enlarge in new windowmelanoma. melanoma

To discover this finding, researchers began their study with five classes of mice. Some of which were injected with melanoma cells, while others had naturally acquired the disease and remained unmanipulated. After the introduction of melanoma, researchers ovariectomized the mice, removing their ovaries to effectively inhibit the natural production of estrogens. This alone was proven to have an effect on the tumor, slowing the tumor's growth.


Then, researchers looked at another two classes of mice. In one class, the mice had intact immune systems, and their counterparts in the second class lacked a total immune system. When an estrogen was introduced to the first class of mice with intact immune systems, it was found that estrogen promotes tumor growth and that removing the production of estrogens by ovariectomy reduced growth. Estrogens were without effect in mice harboring tumors but without an immune system. This suggests that estrogen's role in creating a safe environment for the tumor has nothing to do with its relationship to melanoma cells themselves, but rather it is dependent on its relationship with the immune system.


Upon this discovery, researchers removed the melanoma from the specimens and utilized immune cell profiling technologies to analyze all the immune cells within the tumor itself. When this method was applied to melanoma cells, it was found that the levels of M1 macrophages within the tumor were low, while M2 macrophage levels were high. They were able to show that estrogens drove the polarization of "good" M1 macrophages to "bad" M2 macrophages.


In order to understand macrophages and their effect on a tumor's immunity, it is helpful to think of the tumor as a wound. Because one of estrogen's functions in the body is the promotion of wound healing, it was not totally surprising that the data suggested that estrogens function as they do in wounds. In this metaphor, after the wound is detected, M1 macrophages-the inflammatory macrophages-predominate the healing process, essentially raising alarm bells in the body to call the immune system's attention to the wound. Then, M1 macrophages differentiate into M2 macrophages, in an attempt to heal the wound.


In melanoma and other cancer types, estrogens were shown to accelerate the polarization of M1 into M2 macrophages, which results in the "cloaking" of the tumor hiding it from the body's immune system. This robust polarization also affects the tumor's response to immunotherapy, because the presence of M1 macrophages helps T cells attack the tumor cells. This begs the question: Where are estrogen receptors working, specifically, in the tumor?


To answer this question, researchers created their final class of mice that lacked estrogen receptors in their macrophages. In these mice, the negative effects of estrogens on tumor growth were completely lost. In vitro, researchers took undifferentiated macrophages, known as M0 macrophages, and either added or took away estrogen. When estrogen was applied to the M0 macrophages, they found that estrogen facilitated the polarization of M0 into a M2 phenotype. This robust amount of M2 macrophages not only ceases communication between tumor and immune system, but this lack of communication also suppresses the function of cytotoxic T cells, the very cells that attack the tumor.


To combat this unfavorable polarization of macrophages and to take the brake off the immune system in tumors, the investigators explored the use of estrogen receptor antagonists, more specifically, selective estrogen receptor downregulators (SERDs) as treatments. The most commonly used SERD in cancer treatment is fulvestrant, a drug which until now has been used to inhibit estrogen signaling in ER-positive breast cancers. These new data suggest that this approved drug could have utility in other cancers by reprograming macrophages, thus increasing the efficiency of immune checkpoint therapies. However, with its poor pharmaceutical properties, fulvestrant is unlikely to see widespread use for this application.


"It's got the pharmaceutical properties of ground glass," Donald McDonnell, PhD, from Duke University School of Medicine, said, laughing. "That's a joke in the field, but really it's a very greasy molecule. That's why it has to be given by intramuscular injection and even at that exposure likely limits efficacy."


Fulvestrant is most effective when given as an injection, a treatment that occurs once a month. However, because of its poor pharmaceutical properties, patients must receive a loading dose for the first round of treatment with fulvestrant. A loading dose is essentially two injections that are needed to obtain therapeutically useful levels of fulvestrant. Researchers have found that in a lot of patients the intratumoral levels of fulvestrant (in breast tumors) are not high enough to exert a significant clinical effect.


To provide better options for patients with ER-positive breast cancer, the McDonnell laboratory developed and reported previously a new class of SERDs that function by a different mechanism that does fulvestrant and which are also orally bioavailable. As of this writing, there are twelve new treatments of this class development, the majority of which this group has discovered or been involved in their development. Late phase clinical data for several of these drugs were presented at the 2021 San Antonio Breast Cancer Symposium and, if successful in breast cancer, these drugs will likely be evaluated for their ability to increase the efficacy of immunotherapies in a wide range of cancers.


It has generally been considered that the primary function of endocrine therapies is to inhibit estrogen signaling within tumor cells. However, this new work describing how estrogens impact tumor immunity now suggests that both cancer cell intrinsic and cancer cell extrinsic actions of drugs like fulvestrant may be contributing to efficacy. This suggests that the clinical utility of these drugs may expand to other cancers like colon and lung cancers where immunosuppressive macrophages have been shown to limit responses to immunotherapies.


Elizabeth Rose Galamba is a contributing writer.