Longevity Briefs: Towards Better Cancer Immunotherapy

Longevity briefs provides a short summary of novel research in biology, medicine, or biotechnology that caught the attention of our researchers in Oxford, due to its potential to improve our health, wellbeing, and longevity.

The problem:

Cancer is one of the three deadliest age-related diseases in the world today. Cancer develops when our own cells acquire genetic mutations, so how are our immune systems able to tell cancer cells apart from healthy cells? Since cancer cells mutate frequently, they produce a lot of mutant proteins not found in healthy cells. These proteins, called mutated tumour-specific antigens (mTSAs) allow the immune system to single out cancer cells and destroy them. mTSAs are also a target for cancer treatment. T cells that specifically target a given mTSA can be developed in the lab and administered as a cancer treatment. Alternatively, vaccines can be engineered to prime the immune system to target a particular mTSA.

While this all sounds great, anti-cancer vaccines and other immunotherapy approaches face several problems in practice. Cancerous mutations are random, which means that every patient’s cancer mutates different mTSAs (though there are some common denominators), meaning a personalised approach is required. Furthermore, vaccines designed to help the immune system recognise mTSAs often don’t work as well as it seems they should. When scientists sequence the genomes of cancer cells and look for the predicted mTSAs on the cell surface (where they’d be accessible to immune cells) some mTSAs simply aren’t there. What’s going on? This research aims to address this gap in our knowledge.

The discovery:

Researchers used a powerful combination of proteogenomics (analysing proteins and their genes simultaneously) and mass spectrometry (a technique to identify and quantify proteins) to investigate the tumour antigens in two types of cancer: melanoma and NSCLC (non-small cell lung cancer). They looked at biopsies from 12 and 26 cancer patients respectively. They not only looked for genetic mutations in these samples, but also which mutations were actually translated into antigens presented on the cell surface. Importantly, they didn’t just limit their search to regions of the genome known to encode proteins – they also looked at regions that are normally ignored or cut out of the final protein product, but could become activated in cancer.

What they found was very surprising: of all of the tumour antigens expressed on the surface of the cancer cells, only about 1% of them actually came from mutated sequences. The vast majority of them were antigens encoded by unmutated parts of the genome that are not normally expressed (made into proteins), or that are expressed at much lower levels in healthy cells. In other words, while mutations in the genetic code may be the ultimate cause of cancer, it did not appear that these mutations were expressed at particularly high levels on the cell surface. Rather, the cancer cells were expressing unmutated genes found in healthy cells, but at abnormally high levels, and this is what made up the majority of tumour antigens actually accessible to be recognised by immune cells.

The most common type of surface antigen overall was the aberrantly expressed TSA (aeTSA) – proteins produced from genetic sequences that are normally silent. The researchers also found that aeTSAs were shared among many patients and were also capable of generating an immune response. Healthy donor T cells were able to react to synthetic versions of these antigens, and T cells primed to recognise them were effective at killing cancer cells.

The implications:

This research suggests that the unpredictable effects of targeting mTSAs could be because we are targeting the wrong thing – we should be targeting the tumour antigens that are present on the cell surface, not the ones we predict will be there based on genetic sequencing. While this might sound like an obvious assumption, it has until relatively recently been much easier to rely on genetic sequencing.

So, why was the expression of mTSAs limited? It appeared that many of the mutated sequences were not actually being used to build proteins. Those that were did not get presented on the surface at high levels, so they ended up representing only a very small proportion of what the immune system could actually ‘see’.

This discovery opens up new avenues for immunotherapy development. Targeting aeTSAs could lead to more effective cancer treatments and vaccines, and potentially ones that are more broadly applicable, since these aeTSAs are not randomly mutated and so are common to many different cancer patients. Given that this is a fundamental research discovery, a lot more work and clinical trials will be needed to translate these findings into anything tangible.