Immunologists at Roswell Park identify targetable strategies to reduce metastasis in solid tumor cancers.Roswell Park Comprehensive Cancer Center

BUFFALO, NY — Metastasis, the spread of cancer from one part of the body to another, remains the leading cause of cancer-related deaths. Understanding how solid tumors spread is critical to efforts to improve patient outcomes.a team of scientists led by Dr. Scott AbramsAt the Roswell Park Comprehensive Cancer Center, researchers have uncovered a pathway associated with metastasis to the lung, a common site for cancer to spread. the work, just published in the journal JCI Insightmay have important implications that may point the way to new cancer treatments.

Macrophages are a type of white blood cell that originate from the bone marrow and other tissues in the body and play an important role in maintaining tissue integrity and ensuring effective defenses against diseases such as cancer. The team’s preclinical findings in laboratory models of breast cancer and melanoma reveal new pathways for macrophages that allow these cells of the immune system to be taken up by cancer, leading to increased metastasis to the lung.

“We identified a common population of tissue-resident macrophages in the lung, the alveolar macrophages, through alterations in a pathway known as Wnt/β-catenin,” said Dr. Abrams. He is a member and professor of oncology and co-leader of the Cancer Center, supporting the Roswell His Park Grant Tumor Immunology and Immunotherapy Program. “When this happens, we see enhanced production of a circulating protein called TNF-α, which has long been known to play a complex role, both positive and negative, in cancer immunology.”

Although the role of bone marrow-derived macrophages in metastasis is well described, our understanding of how tissue-resident macrophages contribute to cancer control is less clear.

To test their hypothesis that Wnt/β-catenin expression in alveolar macrophages promotes solid tumor metastasis, Dr. Abrams, the study’s first author, Dr. Elliot Kramer, and colleagues used these We have developed a new approach to genetically alter the expression of this pathway in macrophages. Additional studies confirmed a positive correlation between β-catenin and TNF gene expression.

“Elevation of the Wnt/β-catenin pathway in macrophages promotes metastasis, and TNF-α is a key mediator of that outcome. Based on that relationship, local TNF-α blockade strategies reduce this metastatic outcome.” “We have shown that we can do that,” said Dr. Abrams.

These findings support the use of TNF antagonists (used for the treatment of some autoimmune diseases) as locally delivered, targeted antimetastatic therapy in situations where tumors have developed resistance to the killing effects of TNF-α. It suggests opportunities for repurposing currently approved classes of biologics. .

“Given the expansion of clinical trials targeting Wnt/beta-catenin in oncology, our study is a timely and important advance in this field, exploiting this pathway in alveolar macrophage-solid tumor biology. We believe that we are demonstrating a new mechanism and therapeutic approach to do so,” says Dr. Abrams. “Since the lung is a common site of metastasis in many types of malignancies, we expect our work to have potential relevance across the field of tumor immunology.”

Collaborators include the Paul Klein Immune Intervention Center at Johannes Gutenberg University in Mainz, Germany, and scientists from the Kyoto University Graduate School of Medicine in Kyoto, Japan.

This work was supported by grants from the National Cancer Institute and the National Institutes of Health (project numbers P30CA016056, S10OD025183, R01CA172105, R01CA250412, F30CA254327, F31CA243304, F31CA228396), the Sclarrow Memorial Trust, and the Roswell Park Alliance Foundation.

###

Roswell Park Comprehensive Cancer Center is a community united by the drive to eliminate cancer’s hold on humanity by unlocking the secrets of cancer and unlocking the healing power of hope through a personalized approach. Founded in 1898 by Dr. Roswell Park, it is the only comprehensive cancer center designated by the National Cancer Institute in upstate New York.Click here for details www.roswellpark.org, or 1-800-ROSWELL (1-800-767-9355) or [email protected].