Macrophage “Bodyguard” Disruptors Could Change Breast Cancer Treatment
Summary
- Certain immune cells help breast cancer resist hormone therapy.
- Sylvester Comprehensive Cancer Center researchers studied how blocking those cells with a new drug combo may help.
- The approach could lead to better treatment options for tough-to-treat, hormone therapy-resistant breast cancer cases.
Endocrine therapy has long been a cornerstone for treating estrogen receptor-positive (ER+) breast cancer, which makes up about 75% of all breast cancer cases. Yet, a significant number of patients eventually develop resistance to drugs like tamoxifen, leading to poorer outcomes and limited treatment options.
New research from Sylvester Comprehensive Cancer Center, part of the University of Miami Miller School of Medicine, is shedding light on why this resistance occurs and how it might be overcome by targeting the cellular “bodyguards” in breast cancer cells.
The Role of the Tumor Microenvironment
Sylvester’s research team created two ER+ endocrine therapy-resistant (tamoxifen and fulvestrant) tumor models to understand the resistance mechanism closely. At the heart of this discovery lies the tumor microenvironment (TME). The TME is the “neighborhood” around a tumor, filled with various cells that can either help or hinder cancer growth.
Within TMEs, tumor-associated macrophages (TAMs), a type of immune cell, play a pivotal role. The study, published in Science Translational Medicine, found that a specific subtype of TAMs marked by the proteins CD163 and PD-L1 is more abundant in patients whose tumors resist tamoxifen therapy.
“These macrophages act like bodyguards for the cancer cells, helping them survive treatment,” said Rumela Chakrabarti, Ph.D., the study’s senior author, associate professor in the DeWitt Daughtry Family Department of Surgery and co-director of Sylvester’s Surgical Breast Cancer Research Group. “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.”
Explaining the Science: What Are PD-L1 and DLL1?
• PD-L1 is a protein that helps cancer cells hide from the immune system. Checkpoint inhibitors that block PD-L1 have already changed treatment for some cancers.
• DLL1 is part of the Notch signaling pathway, which helps cells communicate with one another. In this context, DLL1 helps attract and “train” macrophages to support the tumor.
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 as a beacon, attracting macrophages via a CCR3/CCL7-dependent pathway.
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.
Dr. Rumela Chakrabarti
Once in the tumor, these macrophages help maintain cancer stem cells that can regenerate the tumor and are notoriously hard to kill with standard therapies. These immunosuppressive macrophages also lead to the exhaustion of the CD8-T cells, which kill tumor cells.
In both preclinical studies and patient-derived tumor samples, higher levels of DLL1 and PD-L1+ TAMs were strongly associated with resistance to tamoxifen and fulvestrant, another common endocrine therapy. Notably, patients with more of these cells in their tumors had worse survival rates.
Combination Therapy?
To address this challenge, the team conducted preclinical studies to test a new combination therapy. By using antibodies 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.
“This triple therapy approach could be a game-changer for patients whose cancers no longer respond to standard hormone treatments,” said Dr. Chakrabarti. “It’s about hitting the cancer from multiple angles at once.”
From Bench to Bedside
The findings were validated not just in preclinical studies but also in small pieces of tumor tissue from patients grown in the lab. When treated with the triple therapy, these explants showed a marked reduction in both the problematic macrophages and cancer stem cells.
The researchers acknowledge that more work is needed before this approach can be translated into patient care, including extending in vivo modeling and conducting pilot clinical trials.
“Our models are robust, but human tumors are even more complex,” Dr. Chakrabarti noted. “We’re optimistic, but careful.”
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 Dr. Chakrabarti.
“Every breakthrough brings us closer to a future where breast cancer is not just treatable, but truly manageable for every patient,” she said. “We’re committed to making that future a reality in the coming years.”
Tags: breast cancer, breast cancer risk, cancer research, Dr. Rumela Chakrabarti, immune system, SCAN 360, Sylvester Comprehensive Cancer Center