Infection with the Epstein-Barr virus (EBV) is a rite of passage for most of humanity. More than 90 percent of all people on earth contract the virus — most in early childhood — with no ill consequences, because the immune system keeps it under control. When the immune response is dampened by immunosuppressive drugs or diseases such as AIDS, however, the virus can trigger the propulsive cell growth that results in certain lymphomas or other cancers.
A recent study by Dana-Farber scientists describes, for the first time, a mechanism by which EBV infection can lure the immune system into an attack on tumor cells in B cell lymphoma irrespective of whether it is caused by the virus. The findings, published in the journal Nature, not only illustrate that infection can sometimes deter cancer but also suggest ways of improving the immune system’s natural ability to hunt down and destroy B cell cancers.
“Although EBV infection is almost universal in the human population, it’s responsible for only a very small fraction of cancers in people,” says Dana-Farber’s Baochun Zhang, PhD, the senior author of the study. “The immune system is so proficient at keeping the virus in check that it took more than 30 years for researchers to establish that EBV is indeed a tumor virus.”
Mixed signals
Tracing the connection between EBV infection and immune protection against cancer was itself a years-long process. It began with the discovery that EBV carries the genetic blueprints for a protein called LMP1, which serves as the virus’s henchman within infected cells. When EBV infects B cells — the white blood cells that are its favorite target in humans — the rampant production of LMP1 is a giveaway of the virus’s presence.
In 2012, Zhang and his colleagues published a paper showing LMP1 has two major effects in B cells, which seem to be utterly at odds with each other. On the one hand, it spurs the cells to proliferate and sets them on a course for lymphoma. On the other, it orders the immune system to eliminate those very cells.
The finding helped explain why so few human cancers result from EBV infection, but it left open the question of how LMP1 puts the immune system on guard against EBV-infected B cells – what changes does LMP1 make that trigger the immune system’s defense?
That was partially answered in a 2018 paper in which Zhang and his colleagues showed, in animal models, that LMP1 prompts infected B cells to display co-stimulatory molecules that intensify the immune response. For immune system T cells on patrol against infection and cancer, these co-stimulatory molecules provide a warrant for an all-out attack on the infected cells. Not only do CD8+ “killer” T cells join the battle, but CD4+ T cells — known as “helper” cells because they normally play a mainly supportive role — become endowed with killing ability.
Telltale sign
The next step was to determine which of the protein markers, called antigens, on the B cell surface betray the presence of LMP1. Displaying these antigens attracts the immune system’s attention and draws its attack on infected B cells.
“We hypothesized that because LMP1 drives the development of B cell lymphoma, the antigens expressed on the cell surface would be tumor-associated antigens,” Zhang says. (Tumor-associated antigens (TAAs) are found on tumor cells as well as some normal cells; they tend to be present in greater numbers on tumor cells.)
A series of experiments with animal models showed the hypothesis to be correct. Gene-activity tests showed that many of the genes switched on by LMP1 cause a diverse set of TAAs to be displayed on the cell surface. These TAAs signal the presence of a viral infection, but can also indicate cancer. Follow-up experiments showed that the TAAs spark an attack by CD8+ and CD4+ T cells alike.
“Our findings delineate a way that infection with EBV can lead to anti-tumor immunity, with LMP1 playing a key role in the process,” Zhang remarks. The discovery led researchers to conceive a new form of immunotherapy for patients with B cell cancers, particularly those having failed CD8+ T cell-based therapies.
“We theorized that if we collected tumor B cells from a patient and caused them to produce LMP1, they would display more TAAs (and other kinds of tumor antigens) along with co-stimulatory molecules, and thus be able to prime CD4+ T cells also collected from the patient,” Zhang relates. “Infusing the CD4+ T cells back into patients would, we thought, spark an attack on cancerous B cells throughout the body.” When the investigators tested this technique in animal models, it worked precisely as hoped.
Encouraged, the researchers then tested this approach in samples of human chronic lymphocytic leukemia, a prevalent B cell cancer in adults. The results mirrored those in animals, suggesting it holds considerable promise as a treatment for patients. Researchers plan to explore the potential of this approach in future studies.