The area surrounding a tumor—known as the tumor microenvironment (TME)—is a key player in the cancer process. The normal cells of the TME—such as fibroblasts, endothelial cells, adipocytes, and immune cells—play important roles in breast cancer from the very beginning of cancer to recurrence and metastasis, and they impact treatment response and resistance.
At this year’s San Antonio Breast Cancer Symposium (SABCS), BCRF researchers and others reported the latest findings in this promising area and how the TME may be leveraged to improve breast cancer care and outcomes.
Reflecting its importance in breast cancer, prognostic tests have evolved to assess components of the TME. One test called tumor microenvironment of metastases (TMEM is a measure of direct contact between the tumor cell, nearby epithelial cells (tightly packed cells that protect and line organs or blood vessels), and macrophages (a type of immune cell). Their interaction creates a “doorway” that provides a conduit for tumor cells to leave their initial site and migrate to distant sites or metastasize.
Previous studies uncovered an association between high TMEM scores and the presence of distant metastases in estrogen receptor (ER)-positive/HER2-negative breast cancers. Other reports revealed that Black women with ER-positive/HER2-negative breast cancer have a higher risk of distant recurrences (when breast cancer returns and is metastatic) compared to white women. This prompted researchers to examine the relationship between distant recurrence and the TME to see if it could explain this disparity.
At SABCS, a team including BCRF investigator Dr. Joseph Sparano presented their findings in this area. They demonstrated that residual breast cancer after neoadjuvant (pre-surgery) chemotherapy was associated with high TMEM scores and macrophage density for all subtypes of breast cancer. But these factors were higher for Black women compared to white women. The tumors from triple-negative breast cancer (TNBC) , which disproportionately impacts young women and particularly young Black women, consistently had higher TMEM scores and macrophage levels than ER-positive/HER2-negative tumors, providing a potential explanation for why TNBC so often recurs early.
The team also confirmed that high TMEM scores were associated with poorer outcomes across all subtypes. Collectively, these observations suggest that an interplay of components in the TME leads to formation of “TMEM doorways” that enable tumor cells to leave the tumor site. Thus, the increased presence of these “doorways” in Black women compared to white women with ER-positive/HER2-negative breast cancer may be contributing to Black women’s higher rates of metastasis, recurrence, and worse outcomes.
Cancer cells can metastasize or disseminate from the tumor site and recur at distant sites. Some of these cells enter a dormant state where cell growth is suspended or stopped, which allows them to survive for months or years before becoming active again and forming tumors. Researchers are keen to determine how the TME might influence dormancy.
Dr. Jose Javier Bravo-Cordero of the Icahn School of Medicine at Mount Sinai described a series of studies that showed in real-time how breast tumor cells dynamically leave the tumor site. Using cutting-edge imaging technologies, his team was able to visualize mobile tumor cells in the early stages of tumor progression. During his presentation, the SABCS audience watched time-lapsed videos showing how tumor cells enter blood vessels by forming finger-like extensions that can penetrate blood vessel walls—allowing them to spread.
Through extensive studies, Dr. Bravo-Cordero and his team identified a molecule involved in this process—srGAP1—which was previously shown to prevent neuronal cells from elongating (in a manner similar to the finger-like extensions observed as tumor cells spread). Interestingly, cells with low srGAP1 were hypermobile and displayed some characteristics of dormant cells: they remained as single cells or small clusters; their cell growth cycle was halted; and they were positive for a known cell cycle–inhibitor. In addition, the investigators found that srGAP1-low cells use two TME factors to enter and perpetuate the dormant state: TGF-β2, a known driver of dormancy, and macrophages that facilitate the process.
Dr. Bravo-Cordero’s research suggests that the TME, in concert with srGAP1, provides a novel mechanism whereby breast cancer cells can shift from a proliferative to a dormant state. This provides a potential new target for maintaining breast tumor cells in the dormant state or perhaps preventing them from spreading in the first place.
BCRF investigators Drs. Charles Perou, Mafalda Oliviera, Aleix Prat, and their colleagues found that an immune component of the TME (low stromal tumor–infiltrating lymphocytes) and immune gene expression was correlated with patients’ poor response to immune checkpoint inhibitors in hormone receptor–positive/HER2-negative breast cancer. Their finding suggests that components of the TME may predict how tumors will respond to immunotherapies, and studies are underway to test this idea further.
Dr. Vijayakrishna Gadi of the University of Illinois presented his team’s research to test their hypothesis that patients’ anti-tumor responses could be improved by manipulating factors in the TME. The protein TGF-β in the TME prevents immune cells from surrounding and attacking the tumor. Dr. Gadi and his team developed an agent (AMUN-003) that stops TGF-β’s effect and prompts cancer-killing immune cells to travel to the TME. They tested AMUN-003 in combination with immune checkpoint inhibitors for treating TNBC tumors.
In pre-clinical studies with AMUN-003, they demonstrated it was able to almost completely halt tumor progression compared to other similar agents. Combining immune checkpoint inhibitors with AMUN-003 delayed tumor growth and controlled metastatic spread. This is particularly exciting since TNBCs are aggressive and have limited treatment options. Researchers hope further studies will enable AMUN-003’s testing in future clinical trials.
These SABCS presentations help us better understand how breast cancer behaves and reveal potential new strategies for treating it. There is still much to learn about the TME and its role in breast cancer, but researchers are making remarkable progress.
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