Tumours with high somatic mutation burden typically respond better to immune checkpoint inhibitors. However, responses are sometimes observed in patients with a low mutational burden. Yang et al. identified an exceptional responder with metastatic head and neck squamous cell carcinoma (HNSCC) who exhibited complete response to anti-PD1 immunotherapy despite a low mutational burden, and demonstrated that gene fusions were a source of neoantigens in this patient and others.

Whole-genome sequencing and RNA sequencing identified a novel DEK–AFF2 gene fusion. To determine the mechanisms associated with the response, they used a machine-learning approach to test peptides derived from both mutations and gene fusions in the tumour, and found a DEK–AFF2 fusion-derived peptide that stabilized patient-specific HLAs. Expression of DEK–AFF2 led to a cytotoxic response in the patient’s T cells against an HNSCC cell line, and a T cell clone associated with DEK–AFF2 was identified in the patient’s blood using T cell receptor sequencing, suggesting that the response to anti-PD1 treatment was most likely attributable to the DEK–AFF2 fusion.

To extend this to other cancers, the authors looked at 20 head and neck adenoid cystic carcinomas — a cancer type associated with low tumour mutational burden, low immune infiltration and prevalent MYB–NFIB gene fusions. Here, they also identified gene-fusion-derived antigens that elicited cytotoxic T cell responses.

The authors used RNA sequencing data for 30 cancer types with gene fusions from The Cancer Genome Atlas to examine neoantigen presence and its relationship with the immune microenvironment. Of the tumours examined, 24% had a fusion neoantigen predicted to bind to a patient-specific HLA, and there was an inverse relationship between immune cell infiltration and the presence of a fusion neoantigen, suggesting that immunoediting might occur. Indeed, in a cohort of patients with melanoma a comparison of biopsy samples taken both before and during anti-PD1 treatment showed that there was a reduction in the number of fusion neoantigens during immunotherapy, which is possibly indicative of immunoediting against gene-fusion-derived neoantigens.

the findings … could pave the way for novel immunotherapies for other cancers … with … low mutational burden

The authors hope that the findings, which demonstrate that gene fusions are a source of tumour-specific neoantigens, could pave the way for novel immunotherapies for other cancers associated with gene fusions, low mutational burden and an unfavourable immune environment.