Preclinical studies by researchers at Sylvester Comprehensive Cancer Center, part of the University of Miami Miller School of Medicine, showed how a new combination therapy for hormone-resistant, estrogen receptor-positive (ER+) breast cancer can tackle tumors both in mouse models and in patient-derived explants. The team’s studies suggested that a subtype of immunosuppressive tumor-associated macrophage (TAM) help ER+ breast cancer cells resist hormone therapy. They then showed how blocking these cells using anti-DLL1 and anti-PD-L1 antibodies combined with low dose tamoxifen (TMX) resulted in tumor shrinkage, reduce the number of cancer stem cells (CSCs) and reprogramed the immunosuppressive tumor microenvironment (TME) to be less supportive of cancer growth.
Research lead Rumela Chakrabarti, PhD, co-director of Sylvester’s Surgical Breast Cancer Research Group, is senior author of the team’s published study in Science Translational Medicine, titled “DLL1-responsive PD-L1+ tumor-associated macrophages promote endocrine resistance in breast cancer,” in which they say concluded, “Combination therapy with anti-DLL1 and anti–PD-L1 antibodies with TMX reduced tumor growth and associated CSCs and reprogrammed the immunosuppressive TME in both preclinical mouse models and patient-derived explants, thus laying the foundation for a future combined immune-endocrine therapy in these patients.”
Endocrine therapy has long been a cornerstone for treating (ER+) breast cancer, but a significant number of patients eventually develop resistance to drugs such as tamoxifen and fulvestrant, another type of endocrine therapy, leading to poorer outcomes and limited treatment options. “Estrogen receptor-positive (ER+) luminal breast cancer comprises 75% of patients with breast cancer and presents notable treatment challenges because of endocrine resistance,” the authors wrote. “As a result, the five-year survival rate of patients with TMX-resistant breast cancer is only 20%.”
The new research sheds light on why this resistance occurs—and how it might be overcome by targeting the cellular “bodyguards” in breast cancer cells. To better understand the resistance mechanism, the research team focused on the tumor microenvironment and created two ER+ endocrine therapy resistant preclinical tumor models.
The tumor microenvironment can be thought of as the neighborhood surrounding a tumor, supporting various cells that can either help or hinder cancer growth. Within this environment, a type of immune cell called tumor-associated macrophages play a pivotal role, and the researchers found that a specific subtype of TAMs, marked by proteins called CD163 and PD-L1, are more abundant in patients with tumors that are resistant to tamoxifen therapy. The team explained, “In this study, we identified a subtype of immunosuppressive (M2-like) programmed death ligand 1-positive (PD-L1+) tumor-associated macrophages, (TAMs) critically fostering resistance to tamoxifen (TMX) and fulvestrant (FV) through maintaining cancer stem cell (CSC) activity in new mouse models.”
PD-L1 is a protein that helps cancer cells hide from the immune system. Drugs that block PD-L1, known as immune checkpoint inhibitors, have already revolutionized treatment for some cancers. “Immunotherapy involving the anti–programmed death (PD-1)/anti–programmed death ligand 1 (PD-L1) pathway represents a major therapeutic advancement in cancer treatments,” the team stated. “However, immunotherapy in luminal breast cancer is not yet clinically proven.”
Chakrabarti added, “These macrophages act like bodyguards for the cancer cells, helping them survive treatment. By understanding how they are brought to the tumor microenvironment and how they work, we can start to think about new ways to disrupt their support system.”
The research team discovered that these PD-L1+ TAMs are recruited to the tumor by a signaling molecule called DLL1, produced by the cancer cells themselves. DLL1 acts like a beacon, drawing in macrophages through a pathway dependent on CCR3/CCL7. “These TAMs are recruited by Delta-like ligand 1 (DLL1), a Notch signaling ligand expressed in luminal tumor cells, through the CCR3/CCL7 axis,” the investigators further noted.
Once in the tumor, these macrophages help maintain cancer stem cells—cells that can regenerate the tumor and are notoriously hard to kill with standard therapies. These immune suppressive macrophages also lead to exhaustion of the CD8 T cells, which kill the tumor cells.
In both preclinical studies and patient-derived tumor samples, higher levels of DLL1 and PD-L1+ TAMs were strongly linked to resistance against tamoxifen and fulvestrant. Notably, patients with a higher number of these cells in their tumors had worse survival rates. To address this challenge, the team conducted preclinical studies to test a new combination therapy. By using antibodies (Abs) that block DLL1 and PD-L1, alongside low-dose tamoxifen, they were able to shrink tumors, reduce the number of cancer stem cells, and reprogram the immune environment to be less supportive of cancer growth.
Reporting on their studies in mouse models, the team stated, “Our findings collectively suggested that the triple combination treatment with anti-DLL1 Ab, anti–PD-L1 Ab, and TMX represented the most promising therapeutic strategy for effectively targeting DLL1high endocrine-resistant tumor growth, providing the foundation for future clinical trials.” Commenting on their experiments using patient explants, the team further wrote, “Together, these data strongly corroborated our preclinical mouse data and suggested that blocking all three components concurrently in the human setting could lead to responses in endocrine-resistant luminal breast tumors.”
“This triple therapy approach could be a game-changer for patients whose (breast) cancers no longer respond to standard hormone treatments,” said Rumela Chakrabarti, PhD, the study’s senior author and co-director of Sylvester’s Surgical Breast Cancer Research Group. “It’s about hitting the cancer from multiple angles at once.” [Photo by Sylvester Comprehensive Cancer Center]Chakrabarti, who is also an associate professor of surgery at the Miller School, added “This triple therapy approach could be a game-changer for patients whose cancers no longer respond to standard hormone treatments. It’s about hitting the cancer from multiple angles at once.”
The study findings could also help identify patients who may become endocrine resistant, the team suggested. “We propose that coexistence of high DLL1 in tumor cells and high PD-L1 in TAMs could be used to predict high-risk patient groups who may become endocrine resistant.”
The researchers acknowledged that more work is needed before this approach can be translated into patient care by extended in vivo modeling and pilot clinical trials. “Our models are robust, but human tumors are even more complex,” Chakrabarti noted. “We’re optimistic, but careful.” In their paper the authors stated, “Targeting DLL1 alongside anti–PD-L1 Ab and TMX emerges as a promising strategy to overcome endocrine resistance, offering a potential immunotherapy strategy for patients with ER+ breast cancer.”
Understanding the interplay between cancer cells and their microenvironment is crucial for developing next-generation therapies. This research highlights the importance of looking beyond the tumor itself and considering the “ecosystem” that supports it. It’s a reminder that cancer is not just a disease of rogue cells, but of complex cellular communities, said Chakrabarti. “Every breakthrough brings us closer to a future where breast cancer is not just treatable, but truly manageable for every patient. We’re committed to making that future a reality in the coming years.”
The post Macrophage-Blocking Antibodies Help Overcome Breast Cancer Endocrine Resistance appeared first on GEN – Genetic Engineering and Biotechnology News.
