Ancient viral remains in our bodies could help fight lung cancer, study finds

Defensive role of ancient viruses

According to the study, this ancient viral DNA accounts for nearly five percent of the human genome. 

ERVs are mostly dormant, but they are activated when they sense cancerous cells. As a result, an immediate immune response is generated to target and attack the cancer cells. 

The ERVs act much like an alarm system, eliciting an immune response from B cells, which are well-known for producing antibodies to combat infections, such as Covid.

These immune cell mechanisms were studied in mice with cancer as well as in human tumor samples. 

B-cells, which produce antibodies to fight cancer, were identified as playing a critical role by scientists. These cells were discovered around the perimeter of a tumor when studied in the lab. 

Understanding the function of B-cells is critical for the development of more effective and targeted immunotherapy. “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,” said Julian Downward, head of the Oncogene Biology Laboratory at the Crick. 

The findings revealed that "the presence of antibodies targeting ERVs" was associated with longer survival in mice infected with lung cancer during immunotherapy.

This research represents a significant step toward developing more effective treatments for life-threatening lung cancer. 

“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,” said Kassiotis.

The study is published in the journal Nature.

Study abstract:

B cells are frequently found in the margins of solid tumours as organized follicles in ectopic lymphoid organs called tertiary lymphoid structures (TLS). Although TLS have been found to correlate with improved patient survival and response to immune checkpoint blockade (ICB), the underlying mechanisms of this association remain elusive. Here we investigate lung-resident B cell responses in patients from the TRACERx 421 (Tracking Non-Small-Cell Lung Cancer Evolution Through Therapy) and other lung cancer cohorts, and in a recently established immunogenic mouse model for lung adenocarcinoma. We find that both human and mouse lung adenocarcinomas elicit local germinal centre responses and tumour-binding antibodies, and further identify endogenous retrovirus (ERV) envelope glycoproteins as a dominant anti-tumour antibody target. ERV-targeting B cell responses are amplified by ICB in both humans and mice, and by targeted inhibition of KRAS(G12C) in the mouse model. ERV-reactive antibodies exert anti-tumour activity that extends survival in the mouse model, and ERV expression predicts the outcome of ICB in human lung adenocarcinoma. Finally, we find that effective immunotherapy in the mouse model requires CXCL13-dependent TLS formation. Conversely, therapeutic CXCL13 treatment potentiates anti-tumour immunity and synergizes with ICB. Our findings provide a possible mechanistic basis for the association of TLS with immunotherapy response.