In 1909, immunology pioneer and Nobel Prize winner Paul Ehrlich first proposed that, as well as fighting infections, the immune system protects us from cancer.

It was a radical idea. Especially as, at the time, he was unable to prove it. Today, of course, we have a fuller understanding of the role of immune surveillance and cancer eradication. And, indeed, this growing understanding of how our immune system detects newly arising tumours has allowed us to begin to utilise it therapeutically.

One of the most important discoveries – and yet another Nobel Prize winning idea – along the way was that of immune checkpoints by James Allison and Tasuku Honjo. Now well characterised, theses ‘brakes’ which stop killer T cells from killing tumours via checkpoint proteins on the surface of T cells and tumour cells have naturally led to the development of checkpoint inhibitors – immunotherapies that target and disable checkpoint proteins releasing killer T cells to kill their targets.

Many now see immunotherapy as holding the keys to combatting cancer in the long-term as they can be more powerful and less toxic than chemotherapy or radiotherapy. However, there is another layer of immune checkpoints – one that remains untapped for therapeutic purposes.

Epigenetic checkpoints act at the chromatin level to regulate anti-tumour immunity, and I think it is these which could pave the way to a new generation of immunotherapies, cancer vaccines and other medicines for hard-to-treat cancers.

Epigenetic silencing

DNA is packaged into chromatin consisting of histone proteins that form regular nucleosomes like beads on a string. Modifications to chromatin can configure it in an open or closed state – respectively switching on or off genes. Epigenetic silencing refers to chromatin and DNA modifications that result in switching expression of the underlying gene off.

At the heart of epigenetic silencing are retroelements – mobile genetic elements (also known as transposable elements) that have invaded the human genome over millions of years and now amass more than half of our genomic content.

Retroelements have been so successful in expanding their copy number in the human genome because they replicate through an RNA intermediate that then generates a complementary DNA copy which can integrate at random at a different genomic location. Luckily, this is extremely rare because we have evolved a host of defences that protect us from these retroelements. One of the main protective mechanisms are epigenetic silencing pathways, which recognise and target retroelement sequences to switch them off.

Over evolutionary time, therefore, the human genome has been a battleground where genome invasions and epigenetic silencing pathways converge and each new retroelement insertion is spotted and then switched off by the host. This means that a great number of retroelements are never expressed and consequently the human immune system is ignorant to them.

Expression of these retroelements in cancer and the chimeric transcripts that they make distinguishes cancer cells from normal cells, allowing the body’s immune system to target and destroy tumours as they arise, this is the cancer immune surveillance posited so early on by Paul Ehrlich.

Making tumours more visible to the immune system

My and other labs have discovered core epigenetic regulators that target retroelement sequences, switching them off and as such acting as gatekeepers of the human immune system.

These epigenetic regulators – such as TRIM28 and the Human Silencing Hub (HuSH) – can be viewed as checkpoints because if they are inhibited, retroelements are unleashed and can drive an autoimmune response. Indeed, an exciting area of cancer research is in understanding the cascade of molecular events that leads from inactivating a ‘gatekeeper’ epigenetic factor to switching on innate and adaptive immunity that can be harnessed to induce anti-tumour immunity.

These molecular events firstly include chromatin remodelling changes that can affect the chromatin state of the cell and could even impact on cell fate. Secondly, these alterations can result in whole stretches of retroelements shifting from being graveyards of junk inert DNA to becoming hotbeds of highly transcribed nucleic acids that act as immune messengers. Specifically, double-stranded RNAs and RNA:DNA hybrids are generated that resemble culprit pathogen associated molecular patterns from viruses. This is referred to as viral mimicry and serves to induce signalling pathways resulting in the production of type I interferons and NF-kappaB target genes, critical for innate immunity and that support adaptive T cell responses.

Lastly and perhaps most importantly, retroelements and derived chimeric transcripts can encode completely new proteins that have never been seen by the immune system, and these epigenetically silenced antigens could represent cancer vaccine candidates. Through Cancer Research UK funding, many labs including mine can work on these exciting areas of research relevant to translation.

Therapeutic avenues

Conventional immune checkpoints act at the cell-cell interface of tumour cells and killer T cells to prevent T cells from destroying tumours. Inhibitors of these checkpoints in the form of immunotherapies (pembrolizumab for example) have improved patient survival in cancers such as melanomas and lung cancer by enabling a patients’ own immune system to eliminate the tumour without harming neighbouring non-cancerous cells.

Now, an exciting new therapeutic avenue is to target epigenetic checkpoints, which are highly expressed in some cancers to shut-down expression of retroelements and prevent our immune system from eliminating tumours. In fact, it could be that exploiting epigenetic checkpoints may even have more profound effects on patient survival that conventional immune checkpoint blockade because, once expressed, retroelements can activate not only T cells but they can also switch on innate immunity, which contributes to cancer clearance.

Paradoxically, however, epigenetic checkpoints are often downregulated rather than increased in cancers. This can occur naturally during the evolution of a tumour but is thought to also be a consequence of the collateral damaging effects of current cancer therapies such as chemotherapy and radiotherapy. Downregulation of epigenetic checkpoints can lead to chronic activation of retroelements, which we think can make a patient’s immune system dysfunctional.

In my lab, we hypothesize that tumours with epigenetic dysregulation have gained a ground state of tumour immune evasion, which means that they can persist under the radar of immune detection. We propose that studying how tumours exploit downregulation of epigenetic checkpoints to become invisible to the immune system will allow us to discover completely new immune checkpoints in the future that are currently unknown and which we can block in hard-to-treat cancers in patients that don’t respond to current immunotherapies.

I suggest that understanding epigenetic checkpoints of cancer immunity holds the key to harnessing our immune system to eliminate cancer in the long-term.