Metabolism-Regulating Molecule Might Hold Key to Long-Term Effectiveness of Vaccines, Cancer Treatments

BUFFALO, N.Y. — A molecule on the surface of long-lived plasma cells (LLPCs) might not only provide longevity for these important blood cells, but it might be the key to fighting cancer and many viruses, a new study from Roswell Park Comprehensive Center suggests.

A team led by Kelvin Lee, MD, Jacobs Family Chair in Immunology and Senior Vice President for Basic Science at the Buffalo-based cancer center, set out to learn what it is about LLPCs that makes them different from short-lived plasma cells and what those differences might mean for both cancer treatment and fighting viruses. A study detailing what they learned  has been published in the journal Cell Reports.

LLPCs are cells found in bone marrow that allow antibodies against diseases like polio, measles and mumps to provide protection from the time a vaccination is administered throughout a person’s life. The antibodies they make are also important in protecting against newer viruses, like COVID-19. The antibodies from the vaccines themselves only live for a few weeks but have long-term presence in LLPCs, which have a half-life of 3,500 years. They are one of the key resources the body calls on to protect against those disease long-term.

Dr. Lee and team are among the first to examine the differences between short- and long-lived plasma cells.

“These long-lived plasma cells are not intrinsically immortal,” Dr. Lee says. “They’re immortal dependent on specific niches in bone marrow. They are generated in B lymphocytes when you get infected. They’re the most important cells to protect you against epidemics, diseases that show up every 20 years and then disappear.”

But what makes them different? How do they work and why do they live so long? Lee says his team found that the key might be in CD28, a molecule that lives within the bone marrow and activates a plasma cell’s metabolism to become more energy-efficient and long-lasting.

“When CD28 interacts with the molecules CD80 and CD86 in bone marrow, it transmits a signal to the plasma cell that it’s in the right place and turns on a number of programs within the plasma cell that allow it to live for a long time,” Dr. Lee says. “This CD28 signal tells plasma cells to switch over their metabolism to burn fat, which happens to be much more energy-efficient way of powering metabolism.”

These new findings may hold important implications for cancer treatment. Previous research indicates that when CD28 is removed from multiple myeloma cells, chemotherapy is more effective against this cancer.

They may also hold the key to whether a long-lasting and effective vaccine is possible for COVID-19.

“The paper we’ve published identifies what is important for long-lived plasma cells. But the question is, is that not happening with COVID-19?” Lee says. “If that’s not happening, and it’s only creating short-lived plasma cells, what could you do differently to convert short-term plasma cells to a long-lived plasma cell response?”

This project was the doctoral thesis project for the paper’s first author, Adam Utley, PhD, a Roswell Park graduate who is now a researcher with Wake Forest University.

This research was supported in part by grants from two National Institutes of Health agencies: the National Cancer Institute (project nos. CA121044, T32CA085183, CA127910 and CA192844) and the National Institute of Allergy and Infectious Diseases (project no. AI100157).

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