BOSTON - Lymph nodes are critical to the body's immune response against tumors but paradoxically, cancer cells that spread, or metastasize, to lymph nodes can often avoid being eliminated by immune cells. Recent experiments by investigators at Massachusetts General Hospital (MGH) and Boston University School of Medicine provide insights on the details behind this immune evasion, which could help scientists develop strategies to overcome it. The findings are published in Nature Biomedical Engineering.
"We know that lymph nodes are often the first place cancer spreads as it progresses. We also know that our immune system can attack and kill cancer cells," explains senior and co-corresponding author Timothy P. Padera, PhD, an investigator in Radiation Oncology at MGH and a 2021-2026 MGH Research Scholar. "One of the perplexing questions that has been at the core of the recent work in my lab is how can organs that generate our immune responses--lymph nodes--permit cancer cells to survive and take them over instead of attacking them? This was the driving motivation behind this study."
By analyzing patient tissue from breast, colon, and head and neck cancers, combined with animal models of breast cancer lymph node metastases, Padera and his colleagues showed that immune cells called T cells are abundant in metastatic lymph nodes but fail to penetrate tumors that have spread to such nodes. The team measured increased physical forces, known as solid stress, in lymph nodes with metastatic cancer. "We hypothesized that solid stress in lymph node tumors can impair both blood flow and the T cell trafficking capacity of blood vessels in lymph nodes," says lead and co-corresponding author Dennis Jones, PhD, an assistant professor of Pathology & Laboratory Medicine at the Boston University School of Medicine.
The scientists then developed a device to compress lymph nodes in order to simulate the gradual growth of lymph node metastases. When they applied compressive force to lymph nodes, there was a clear link between physical force and disruption of T cell entry into lymph nodes. "Our findings indicate that as cancer cells grow in the lymph node, they reorganize and alter the lymph node, disabling critical functional responses of the immune system," says Padera. "By understanding how cancer cells are disabling lymph node function, we hope to fight back to help the lymph nodes generate anti-cancer immune responses, which will help fight cancer cells everywhere in the body."
Alleviating solid stress with the blood pressure drug losartan boosted the numbers of blood vessels and T cells in lymph node metastases, suggesting that alleviating solid stress is a potential strategy to improve T cell entry into tumors.
"Our work now leads to many important additional questions," says Jones. "Does losartan treatment combined with immunotherapy cause the eradication of metastatic cancer cells in lymph nodes by T cell killing? And further, does this lead to a strong systemic anti-cancer immune response that helps clear the cancer from the entire body?" Jones notes that finding the answers to these questions could lead to new treatment strategies for patients with metastatic cancer.
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Padera is an associate professor of Radiation Oncology at Harvard Medical School. In addition to Jones and Padera, co-authors include Zixiong Wang, Ivy X. Chen, Sue Zhang, Rohin Banerji, Pin-Ji Lei, Hengbo Zhou, Victoria Xiao, Cecilia Kwong, Jan Willem M. van Wijnbergen, Ethel R. Pereira, Benjamin J. Vakoc, Peigen Huang, and Hadi T. Nia.
This study was supported by the National Institutes of Health, the Massachusetts General Hospital Executive Committee on Research, the Mass General Research Institute Research Scholars Program, and the METAvivor organization.
About the Massachusetts General Hospital
Massachusetts General Hospital, founded in 1811, is the original and largest teaching hospital of Harvard Medical School. The Mass General Research Institute conducts the largest hospital-based research program in the nation, with annual research operations of more than $1 billion and comprises more than 9,500 researchers working across more than 30 institutes, centers and departments. In August 2020, Mass General was named #6 in the U.S. News & World Report list of "America's Best Hospitals."
About Boston University School of Medicine
Originally established in 1848 as the New England Female Medical College, and incorporated into Boston University in 1873, Boston University School of Medicine (BUSM) today is a leading academic medical center with an enrollment of more than 700 medical students and approximately 1,150 students pursuing degrees in graduate medical sciences. BUSM faculty contribute to more than 605 active grants and contracts, with total anticipated awards valued at more than $200 million in amyloidosis, arthritis, cardiovascular disease, cancer, infectious diseases, pulmonary disease and dermatology, among other areas. The School's teaching affiliates include Boston Medical Center, its primary teaching hospital; Boston VA Healthcare System; St. Elizabeth's Medical Center in Brighton, Mass.; Kaiser Permanente in northern California; plus Boston HealthNet, a network of 15 community health centers. For more information, please visit http://www.bumc.bu.edu/busm/
Journal
Nature Biomedical Engineering