Researchers at the UCLA Jonsson Comprehensive Cancer Center have found that a drug that activates the body's natural defences by behaving like a virus may also make certain stealthy melanoma tumours visible to the immune system, allowing them to be better targeted by immunotherapy.
The findings, published today in the journal Science Translational Medicine, open up the possibility of using drugs that mimic viruses to overcome immunotherapy resistance in tumours with defective interferon signalling and help create more personalised therapies for people with hard-to-treat cancers.
"Most immunotherapy approaches rely on the ability of T cells to recognise and kill tumour cells," said lead and corresponding author Dr. Anusha Kalbasi, an assistant professor of radiation oncology at the David Geffen School of Medicine at UCLA and member of the Jonsson Cancer Center.
"But in some patients, tumours escape the immune system through mutations in genes involved in the interferon signalling pathway. This is a critical pathway because it normally allows tumours to increase their antigen presentation, an intricate machinery that makes tumours visible to T cells."
Interferons are proteins in cells that respond to viral infection by impeding the virus's ability to replicate and alerting the immune system to marshal its forces.
Activating interferon signalling in tumours helps slow down tumour division and can lead to the release of molecules that recruit more immune cells to the tumour.
"This coordinated effort as a result of interferon signalling can help the immune system better identify and kill tumour cells," Kalbasi said.
The team first attempted to overcome defective interferon signalling by using adoptive T cell therapy, a type of immunotherapy that involves extracting T cells from a patient and engineering them in the laboratory to recognise and kill cancer cells.
The researchers found that these T cells remained ineffective against tumours with defective interferon signalling.
The authors then engineered mouse melanoma tumour cells with a gene called NLRC5.
NLRC5 increased antigen presentation even in the absence of interferon signalling and restored the effectiveness of the T cells.
While this approach was effective in mice, engineering tumour cells in humans was not as simple.
Instead, Kalbasi and his colleagues turned to a virus-mimicking drug called BO-112 that activates virus-sensing pathways in tumours.
When the drug was injected directly into the tumour in the laboratory, the team discovered that the activation of virus-sensing pathways increased antigen presentation even when interferon signalling was defective.
As a result, these tumours could be recognised and killed by T cells.
"This study helps us understand the interdependence between interferon signalling and antigen presentation, which gives us important insights into how tumour cells are recognised by the immune system," said the study's senior author, Dr. Antoni Ribas, a professor of medicine at the Geffen School of Medicine and director of the tumour immunology program at the Jonsson Cancer Center.
"New strategies to promote antigen presentation to make tumours more visible to the immune system will allow immunotherapy to be effective for even more tumour types."
The findings also highlight the potential of other promising clinical approaches that bypass tumour interferon signalling and antigen presentation, like CAR, or chimeric antigen receptor-based T cell therapy, which can recognise and kill tumour cells even in absence of antigen presentation.
Kalbasi is now leading a human clinical trial of the combination therapy of nivolumab, an immune checkpoint blockade drug, and BO-112 in people with certain types of sarcoma who are undergoing radiation followed by surgery.
The idea is to activate the immune system against the patient's tumour while the tumour is still in the body.
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