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Checkpoint Immunotherapy Response Described in Tumors with Gene Fusion-Based Neoantigens

NEW YORK (GenomeWeb) – A team from Memorial Sloan Kettering Cancer Center (MSKCC) and the University of Gothenburg have demonstrated that new antigens formed from gene fusion events can prompt a T cell immune response against head and neck cancers and other tumor types, raising the possibility of using checkpoint blockade immunotherapy to treat some fusion-positive tumors.

"[W]e demonstrate that gene fusions are a source of immunogenic neoantigens that can mediate responses to immunotherapy," co-senior and co-corresponding authors Luc Morris and Timothy Chan, human oncology, pathogenesis, immunogenomics, and precision oncology researchers at MSKCC, and their colleagues wrote.

As they reported online today in Nature Medicine, the researchers used whole-genome sequencing, exome sequencing, T cell receptor sequencing, and/or RNA sequencing to profile a large set of head and neck squamous cell carcinoma (HNSCC) tumors, after identifying a metastatic head and neck cancer patient at MSKCC who had an exceptional, complete response to the anti-PD-1 immune checkpoint-inhibiting antibody pembrolizumab (marketed as Keytruda by Merck).

The patient's tumor tested negative for dozens of human papillomavirus serotypes, showed low immune cell infiltration, and lacked PD-L1 immune checkpoint staining, the investigators explained. When they did genome sequencing on a frozen sample from the patient's primary tumor, though, they saw hints of a novel gene fusion between the DEK and AFF2 genes — an alteration that was verified with additional RNA sequencing and fluorescence in situ hybridization.

That analysis was helped along by RNA-seq data for another 521 head and neck squamous cell carcinomas profiled for the Cancer Genome Atlas project, which made it possible to look at everything from immune cell infiltration, T cell activation, the DEK-AFF2 fusion, and other features that might impact immune response.

The HNSCC results suggested the immune system can respond to tumors containing fusion-related neoantigens, even in the absence of other linked immune response to tumors, such as enhanced mutational loads or pronounced immune cell infiltration. In particular, the team saw  signs of cytotoxic T cell activity that appeared to target the DEK-AFF2 fusion neoantigen.

The researchers identified additional gene fusions using RNA-seq data on 20 frozen tumors samples from patients with minimally-mutated and -immune infiltrated adenoid cystic carcinoma head and neck cancers, before turning their attention to transcriptome and exome sequence data for tumors from dozens more cancer types assessed by TCGA.

In a collection of more than 5,800 tumors with documented gene fusions, for example, they reportedly found neoantigen-producing fusions in almost a quarter of the cases. The gene fusion neoantigens appeared to be more common in cases with immune-depleted microenvironments, or apparent loss of heterozygosity involving the human leukocyte antigen (HLA) immune locus.

"Although the determinants of the tumor immune microenvironment are complex and multifactorial, these results reveal a significant inverse association between measures of adaptive immunity and the presence of a fusion neoantigen," the authors wrote.

The team went on to explore the relationship between immune editing and fusion-based neoantigens, evaluating pre- and post-treatment samples from melanoma patients who received pembrolizumab anti-PD-1 checkpoint blockade immunotherapy. There, fusion neoantigens appeared to decline following treatment, particularly in patients responding to the treatment. 

"These findings highlight an important class of tumor-specific antigens and have implications for targeting gene fusion events in cancers that would otherwise be less poised for response to immunotherapy, including cancers with low mutational load and minimal immune infiltration," Morris, Chan, and their co-authors wrote.

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