Duke Cancer Institute researchers have uncovered a previously unappreciated role for estrogens in promoting tumor growth and suppressing immune responses across multiple cancer types, including triple-negative breast cancer, melanoma, and colon cancer. The study, published in Science Advances, reveals that estrogens decrease the presence of eosinophils, a type of white blood cell crucial for anti-tumor immunity, potentially reducing the effectiveness of immunotherapies. These findings suggest that anti-estrogen therapies could enhance immunotherapy efficacy in a broader range of cancers than previously thought.
Estrogens and Immune Suppression
The research team, led by Donald McDonnell, PhD, demonstrated that estrogens contribute to tumor growth even in cancers lacking estrogen receptors. By analyzing patient data and conducting experiments in mouse models, they found that estrogens reduce the number of eosinophils within tumors. Increased eosinophil presence, known as tumor-associated tissue eosinophilia (TATE), is linked to improved patient outcomes in various cancers, including colon, esophageal, gastric, oral, melanoma, and liver cancers. The study showed that estrogens decrease both eosinophil numbers and TATE in mice.
Reversing Estrogen's Effects
The researchers discovered that anti-estrogen drugs could reverse the immunosuppressive effects of estrogens, restoring the immune system's ability to target and destroy tumors. This reversal enhanced the effectiveness of immunotherapies, leading to slowed tumor growth in preclinical models. "Here we have found a simple way to bolster the effectiveness of immunotherapy for this type of breast cancer, and the benefit was even seen in other cancers, including melanoma and colon cancers," said McDonnell.
Clinical Trial with Lasofoxifene
Based on these promising results, the Duke team is planning a clinical trial to assess the efficacy of lasofoxifene, an investigational anti-estrogen drug, in patients with triple-negative breast cancer. This trial aims to evaluate whether lasofoxifene can enhance the immune response to immune checkpoint inhibitors (ICBs). Up to 50 TNBC patients will receive lasofoxifene before starting standard therapies, with biopsies and blood work used to monitor immune response markers, including eosinophils.
Broader Implications for Cancer Treatment
The implications of this research extend beyond triple-negative breast cancer. The estrogen-blocking strategy could potentially improve treatment outcomes for other cancers, including melanoma, colon, lung, head, and neck cancers. By enhancing the efficacy of existing immunotherapies, this approach could also reduce the reliance on chemotherapy, known for its toxic side effects.
Impact on Eosinophil Biology
"These findings establish the importance of ER (estrogen receptor) signaling in eosinophils on tumor pathobiology and highlight the potential utility of combining ER modulators with (immune checkpoint blockades) in patients with breast cancer and other cancers where the presence of TATE is beneficial," the researchers concluded. The study underscores the importance of considering hormonal influences on immune cells within the tumor microenvironment and opens new avenues for developing more effective cancer treatments.
