Immune system to Epstein-Barr virus-fueled cancers: “I’ve got an eye on you”

In the vast majority of us, the Epstein-Barr virus (above) causes mild illness and never bothers us again. However, it can lay dormant in small numbers of B cells for years, waking up if the immune surveillance keeping it in check is broken and fueling lymphomas. (NCI)

Some 90 percent of us are exposed to the Epstein-Barr virus (EBV) at some point in our lives. While the immune system’s T cells rapidly clear most EBV-infected B cells, about one in a million infected cells escapes destruction. Within these cells, the virus enters a latent phase, kept in check by the watchful eye of so-called memory T cells.

This uneasy relationship usually holds steady for the rest of our lives, unless something suppresses the immune system – such as infection with HIV or use of anti-rejection drugs after a transplant – and breaks the surveillance. The virus can then reawaken and drive the development of certain B cell cancers.

How do our T cells keep their watch? For some years there have been inklings as to the target of their surveillance, but now we have definitive evidence: A team led by Klaus Rajewsky of the Program in Cellular and Molecular Medicine (PCMM) at Children Hospital Boston and the Immune Disease Institute (IDI) has conclusively pinned the role on a viral protein called LMP1.

Rajewsky and his team had long suspected LMP1 as the telltale molecule – it’s also known to play a role in transforming B cells into lymphoma cells. But they had little success when they tried to mimic latent EBV infection by engineering mice whose B cells produced LMP1.

“We were never able to get the mice in our models to actually produce any mature B cells.” explains Rajewsky, who recently moved to the Max Delbrück Center for Molecular Medicine in Germany, “The immune response against the LMP1-producing B cells was so robust that the cells were eliminated very early on.”

Their breakthrough came when postdoctoral fellow Baochun Zhang re-engineered the same LMP1-producing mice to lack T cells. “The mice were initially fine, but succumbed within two to three months to aggressive B cell lymphomas,” Rajewsky says. “The profile mimicked very closely what we see in immunosuppressed lymphoma patients.

Apart from allowing Rajewsky and his colleagues to finally prove what they had long believed – that the immune system relies on LMP1 to keep an eye on latent EBV infections – the model also provided some surprising clinical insights.

First, Rajewsky noted in the mouse model that LMP1-producing B cells came under attack from an unexpected group of T cells: helper T cells, which display a marker called CD4. Such cells rarely carry out immune attacks on their own, but rather support other front-line cells such as natural killer (NK) cells or T cells with the CD8 marker (also called cytotoxic T cells). When immunosuppressed patients develop EBV-driven lymphomas, they are often treated with autologous CD8+ T cell infusions: some CD8+ cells are extracted from their blood, grown up in a laboratory, and given back to them.

“These results would argue for also considering CD4+ T cells for treatment,” Rajewsky says.

Second, the team found that cancerous B cells in the LMP1-producing mice often displayed targets that attract NK cells. Seeing an opportunity, Rajewsky worked with cancer immunologist Glenn Dranoff and colleagues at Dana-Farber Cancer Institute to test a “fusion” protein that takes an antibody and replaces its binding end with a portion of the NK cell’s activating receptor. The mashup attaches to the NK targets on the cancer cells and uses its antibody backbone as a transmitter to call in the whole range of immune system players, thereby activating and directing a vigorous immune assault against the cancer cells. In a separate model of LMP1-fueled lymphomas, the fusion prolonged survival in mice while reducing tumor growth.

“These preclinical results suggest administration of the fusion protein, perhaps combined with treatment with CD4+ T cells, could benefit some patients with EBV-driven lymphomas,” according to Rajewsky.