Immunogenic neoantigens derived from gene fusions stimulate T cell responses

Abstract

Anti-tumor immunity is driven by self vs. non-self discrimination. Many immunotherapeutic approaches to cancer have taken advantage of tumor neoantigens derived from somatic mutations. Here, we demonstrate that gene fusions are a source of immunogenic neoantigens that can mediate responses to immunotherapy. We identified an exceptional responder with metastatic head and neck cancer who experienced a complete response to immune checkpoint inhibitor therapy, despite a low mutational load and minimal pre-treatment immune infiltration in the tumor. Using whole genome sequencing (WGS) and RNA sequencing (RNA-seq), we identified a novel gene fusion, and demonstrated that it produces a neoantigen that can specifically elicit a host cytotoxic T cell response. In a cohort of head and neck tumors with low mutation burden, minimal immune infiltration, and prevalent gene fusions, we also identified gene fusion-derived neoantigens that generate cytotoxic T cell responses. Finally, analyzing additional datasets of fusion-positive cancers, including checkpoint inhibitor-treated tumors, we found evidence of immune surveillance resulting in negative selective pressure against gene fusion-derived neoantigens. 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.

T cell receptor‐based cancer immunotherapy: Emerging efficacy and pathways of resistance

“…A final class of antigens, termed cancer neoantigens, 197 are derived from somatic genomic events resulting in non-synonymous point mutations, [4][5][6]8,12,18,198 insertions, 199 gene fusions, 200 or alternative RNA editing. 201 Because neoantigens are exclusive to tumor cells, the risk of on-target/off-tumor injury to healthy tissues is minimized.…”

Targeting fusions for improved outcomes in oncology treatment

“…Indeed, fusions have been Cancer March 15, 2020 suggested to be important for neoantigens, which generate cytotoxic T-cell responses and can help to mediate responses to immunotherapy. 31 The current study was limited by the small sample size among the UCSD patient population, but a significant difference nevertheless was found between therapies targeting fusions and those not targeting fusions. Differences in the specific fusions found between patients in the group matched to other alterations versus those matched to fusions also may have contributed to the difference noted between these groups.…”

“…The presence of a fusion may provide additional targets beyond the fusion itself. Indeed, fusions have been suggested to be important for neoantigens, which generate cytotoxic T‐cell responses and can help to mediate responses to immunotherapy …”

The immunogenic potential of recurrent cancer drug resistance mutations: anin silicostudy

“…We asked whether these immunogenic properties could be shared by a larger number of cancer drug resistance mutations and when considering individuals featuring a much larger number of class I HLA allotypes. Using in silico predictions, for the first time, we present a general survey of the immunogenicity of 226 missense resistance mutations associated with several genes (19), tissues (9) and tumor subtypes (27). We show that many of these mutations generate neopeptides that are predicted to be HLA-presented by a large proportion of the general population.…”

“…Although the clinical development of vaccination strategies against TAAs continues, they are now generally regarded as less-than-ideal and often weak effectors, primarily because of incomplete tumour specificity and partial central tolerance 13,19 . Increasingly, researchers are focusing their attention on cancer-specific peptides such as those associated with passenger mutations 10,[20][21][22][23][24][25][26] , somatic gene fusions 27 , aberrantly expressed tumor transcripts 28 and tumor-specific alternatively spliced isoforms 29 and posttranslational modifications 30, 31 .…”