Tassie Devils Hold Clue for How Human Cancers Evade the Immune System

Melbourne researchers from Peter Mac, in collaboration with Cancer Research UK, have uncovered a new way that some human cancers can hide from the body’s immune system, a feature they share with tumours from an unlikely source – the Tasmanian devil.

In this new study just published in the journal Cancer Cell, scientists discovered that some human, mouse and Tasmanian devil cancers can reduce the amount of immune-stimulating MHC Class I (MHC-I) proteins present on their surface, effectively masking them from being recognised and destroyed by killer immune cells.

“By avoiding recognition by immune cells, some cancers can continue to grow unchecked and are less likely to respond to new types of immune-based cancer therapies,” says Dr Marian Burr, who began this research at the University of Cambridge, UK, and completed it at Peter Mac.

“Identifying how and why some tumours undergo this process of hiding from the immune system may help to improve treatment outcomes.”

Peter Mac's Dr Marian Burr
Peter Mac’s Dr Marian Burr

Whether or not MHC-I appears on the cell surface can depend on the activity of other proteins inside the cell. By systematically knocking out all the genes in the human genome using cutting-edge CRISPR-Cas9 technology, the researchers looked for clues as to which proteins were important in controlling MHC-I at the surface.

They found that a group of proteins that collectively form an epigenetic protein complex – known as PRC2 – acts inside the cell to switch off the genes required for MHC-I production.

When they looked in human cancers such as lung cancer, neuroblastoma and Merkel Cell Cancer they found that tumours with high levels of PRC2 proteins had reduced MHC-I and this was associated with an impaired ability of tumour-killing immune cells to recognise these cancers.

What was especially surprising is that they found the exact same process also occurs in mouse models of lung cancer and in Tasmanian devil facial tumours, a deadly cancer of the mouth and face that has decimated the wild Tasmanian devil population.

“Similar to some human cancers, a defining feature of Tasmanian devil facial tumours is a remarkable ability to evade recognition and destruction by the immune system,” says Dr Burr who was lead author on the study.

“This feature of devil facial tumours, and some human cancers, is a powerful mechanism of immune evasion that is conserved in different species throughout the process of evolution.”

When the researchers used targeted drugs to effectively shut down the PRC2 pathway in a mouse model of small cell lung cancer, they found they could re-establish MHC-I expression which led to more effective immune-mediated tumour cell killing.

Professor Mark Dawson, Consultant Haematologist and head of the Cancer Epigenetics group at Peter Mac, said this discovery suggests a new way to make the human immune system see cancers that are currently invisible.

Professor Mark Dawson
Professor Mark Dawson

“The good news here is that suppression of MCH-I in this context is reversible, which means that cancers previously invisible to the immune system could be re-exposed using approaches to increase levels of the MHC-I components,” says Prof Mark Dawson, who is senior author on the study.

“It is hoped this discovery may lead to a rationale for combining drugs that shut down the PRC2 pathway with immunotherapies to treat some aggressive cancers. This is especially important for solid cancers that are notoriously resistant to immune-based therapies, such as small cell lung cancer and some types of paediatric cancers, that have low expression of MHC-I.”

The paper, titled ‘An evolutionarily conserved function of polycomb silences the MHC class I antigen presentation pathway and enables immune evasion in cancer’, has been published online by Cancer Cell.

This article originally appeared on the Peter Mac website. Thanks to the generosity of our supporters, Australian Cancer Research Foundation has provided four grants to Peter Mac, totalling $9 Million for cutting edge cancer research equipment and technology.