Nature Genetics study of Prof. Jimmy Van den Eynden questions neoantigen depletion in the untreated cancer genome

CRIG researcher Prof. Jimmy Van den Eynden recently published a top article in the high impact journal Nature Genetics about (the lack of) neoantigen depletion signals in the untreated cancer genome.

Prof. Van den Eynden explains: ‘Cancer is caused by somatic mutations. Some of these mutations result in the formation of neoantigens, small peptides that are presented at the tumour cell surface via HLA molecules. Recognition of these neoantigens by immune cells results in cancer cell elimination, a response that is boosted by cancer immunotherapy. These tumour-immune interactions are expected to impose an immunogenic negative selection pressure on the underlying mutations during tumour evolution, leading to neoantigen depletion.

To determine the extent of this neoantigen depletion in cancer, we performed a systematic analysis using exome sequencing data from +/- 10.000 untreated primary tumours and 32 different cancer types from The Cancer Genome Atlas. We found complex correlations between a somatic mutation’s DNA sequence context and the HLA-binding capacity of the translated peptides, resulting in biased findings when improper background mutation rate models are used. Using newly developed selection metrics, we showed that, contrary to what is commonly believed, neoantigen depletion signals are in fact weak to absent.

These results suggest the presence of efficient immune evasion mechanisms early during tumour evolution. It remains to be determined how these immunogenic selection pressures are influenced by sudden changes in the tumour microenvironment, as occur during immunotherapy or following metastatic spread.

As HLA affinity predictions are increasingly used to study immunogenic selection during tumour evolution, our findings have important implications for proper interpretation of related studies.’

You can read the full article here and the 'behind the paper' commentary here.