Targeting ‘viral footprints’ in our DNA could boost cancer treatment

Remnants of ancient retroviruses passed down in our DNA could be an effective target for antibodies against lung cancer, according to new findings from researchers at the Francis Crick Institute, published in Nature this week.

This research, part-funded by Cancer Research UK, could further our understanding of different patient responses to immunotherapy treatments and also improve these treatments for the future.

Checkpoint inhibitors are a type of immunotherapy sometimes given to people with lung cancer to block the proteins that prevent the immune system from attacking tumours. But it can be very hard to predict who will respond to this type of treatment.

The research team in collaboration with scientists at UCL, set out to understand the link between better responses to immunotherapy and the presence of antibody-producing B cells around the perimeter of a tumour.

They investigated immune cell activity in mice with lung cancer and also in tumour samples from people with lung cancer collected as part of the Cancer Research UK funded TRACERx study. They found that B cells contribute to the immune response to lung cancer through the production of tumour-binding antibodies, in a manner similar to how B cells produce anti-viral antibodies following flu or SARS-CoV-2 vaccination.

When they investigated the target of this immune response, they found that these antibodies recognised proteins expressed by ancient viral DNA, called endogenous retroviruses (ERVs). This viral DNA makes up around 5% of the human genome, passed down from the historic infections of our ancestors. The viral genes are silenced in the majority of healthy tissue, but in cancers they can be woken up.

Katey Enfield, postdoctoral training fellow at the Crick and joint first author with PhD students Kevin Ng and Jesse Boumelha, said: “There is a huge focus on the activity of T cells against cancer because of their ability to destroy tumour cells. But our work highlights an important role for antibody responses and also how these responses might be boosted with immunotherapy.

“Our study also helps to explain the mechanism by which the presence of B cells in tumours improves patient response to immunotherapy.”

The team also looked into the impact of the B cell activity and expression of ERVs in response to checkpoint inhibition immunotherapy. They found that the presence of antibodies targeting ERVs is associated with extended survival in mice with lung cancer when treated with immunotherapy, and that ERV expression is a predictor of response to checkpoint inhibitors in patients.

Julian Downward, Associate Research Director and head of the Oncogene Biology Laboratory at the Crick, said: “This work opens up a number of new opportunities for improving patient responses to immunotherapy, a crucial step in helping more people survive lung cancer.

“We now know that areas of B cell expansion can help us predict a positive response to checkpoint inhibition and with more research, we could work to boost B cell activity in a targeted way for the patients less likely to respond.”

George Kassiotis, head of the Retroviral Immunology Laboratory at the Crick, said: “ERVs have been hiding as viral footprints in the human genome for thousands or millions of years so it’s fascinating to think that the diseases of our ancestors might be key to treating diseases today.

“With more research, we could look to develop a cancer treatment vaccine made up of activated ERV genes to boost antibody production at the site of patient’s cancer and hopefully improve the outcome of immunotherapy treatment.”