Targeting historic infections in 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 a new study by researchers at UCL and the Francis Crick Institute.

The research, published in Nature and part-funded by Cancer Research UK, could improve our understanding of why patients respond differently to immunotherapy treatments - allowing the therapies to be improved for the future.

One type of immunotherapy, known as checkpoint inhibitors, is sometimes given to people with lung cancer to block to proteins that prevent the immune system from attacking tumours. But it can be difficult to predict which patients will respond to this type of treatment.

The research team wanted to investigate 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 alongside 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 similar way to how B cells produce anti-viral antibodies following flu or SARS-CoV-2 vaccination.

The team 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.

The team also investigated the impact of 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.

Professor Charles Swanton (UCL Cancer Institute, the Francis Crick Institute and Cancer Research UK) "This work emphasises the importance of B cells in immune surveillance and checkpoint inhibitor response, revealing a class of antigens that may in the future be used to optimise tumour immune control. These exciting findings were made possible by the support of UCL and UCLH in sponsoring the TRACERx national cancer evolution clinical program over the last 9 years"

Dr Julian Downward (Head of the Oncogene Biology Laboratory at the Crick), said: "This work opens up a number of new opportunities for improving patients’ 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."

Postdoctoral training fellow and joint first author, Katey Enfield (The Francis Crick Institute), 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."

Researchers hope that the findings may one day help develop a cancer treatment vaccine.

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 a patient’s cancer and hopefully improve the outcome of immunotherapy treatment."
  • University College London, Gower Street, London, WC1E 6BT (0) 20 7679 2000