Neoantigens derived from oncogenic gene fusions can elicit T-cell responses in tumors with low TMB.
Major finding: Neoantigens derived from oncogenic gene fusions can elicit T-cell responses in tumors with low TMB.
Concept: Gene fusions represent a source of tumor-specific neoantigens.
Impact: Oncogenic gene fusions expressed in tumors may have therapeutic potential for immunotherapy.
Antitumor immunity is mediated by the recognition of tumor-specific neoantigens by cytotoxic T cells. For this reason, immune checkpoint inhibitor therapies are generally more effective in cancers with high tumor mutational burden (TMB). Gene fusions are oncogenic drivers in many cancers with low TMB but have not been identified thus far as a source of neoantigens despite the likelihood that that they would produce neoantigens more immunogenic than those derived from missense mutations. Yang, Lee, Srivastava and colleagues identified a novel DEK–AFF2 gene fusion in a patient with head and neck squamous cell carcinoma whose tumor had low TMB and minimal immune infiltrate but a complete response to the anti–PD-1 antibody pembrolizumab. Analysis of predicted HLA-restricted peptides revealed a DEK–AFF2-derived peptide that stimulated the activation of T cells from the patient. The fusion peptide was responsible for the response to anti–PD-1 treatment and tumor regression. To study gene fusion–derived neoantigens in other cancers with low TMB, a panel of adenoid cystic carcinoma head and neck cancers expressing MYB–NFIB fusions was screened for HLA-A2–restricted peptides. The screen uncovered three peptides derived from the MYB–NFIB fusion and one peptide derived from an NFIB–MYB fusion. T cells from peripheral blood mononuclear cells of a patient expressing the MYB–NFIB fusion showed reactivity to the fusion peptide. The presence of fusion-derived peptides was further analyzed in 30 cancer types in The Cancer Genome Atlas. Fusion-derived HLA-predicted peptides were found in 24% of all fusion-expressing cancers and were most likely to be detected in the presence of low immune surveillance. In addition, analysis of a cohort of tumors from patients with melanoma treated with anti–PD-1 therapy revealed additional predicted fusion neoantigens that were observed to be eliminated during successful treatment. Collectively, these results propose gene fusions that are expressed in low TMB cancers as a source of immunogenic neoantigens that can elicit T-cell responses and potentially have important implications for designing immunotherapeutic approaches.
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