Abstract
BackgroundEfficient identification of neoantigen-specific T-cell responses in epithelial ovarian cancer (EOC) remains a challenge. Existing investigations of spontaneous T-cell response to tumor neoepitope in EOC have taken the approach of comprehensive screening all neoantigen candidates, with a validation rate of 0.5–2%.MethodsWhole-exome and transcriptome sequencing analysis of treatment-naive EOC patients were performed to identify neoantigen candidates, and the immunogenicity of prioritized neoantigens was evaluated by analyzing spontaneous neoantigen-specfic CD4+ and CD8+ T-cell responses in the tumor and/or peripheral blood. The biological relevance of neoantigen-specific T-cell lines and clones were analyzed by evaluating the capacity of autologous ovarian tumor recognition. Genetic transfer of T-cell receptor (TCR) from these neoantigen-specific T-cell clones into peripheral blood T-cells was conducted to generate neoepitope-specific T-cells. The molecular signature associated with positive neoantigen T-cell responses was investigated, and the impacts of expression level and lymphocyte source on neoantigen identification were explored.ResultsUsing a small subset of prioritized neoantigen candidates, we were able to detect spontaneous CD4+ and/or CD8+ T-cell responses against neoepitopes from autologous lymphocytes in half of treatment-naïve EOC patients, with a significantly improved validation rate of 19%. Tumors from patients exhibiting neoantigen-specific T-cell responses exhibited a signature of upregulated antigen processing and presentation machinery, which was also associated with favorable patient survival in the TCGA ovarian cohort. T-cells specific against two mutated cancer-associated genes, NUP214 and JAK1, recognized autologous tumors. Gene-engineering with TCR from these neoantigen-specific T-cell clones conferred neoantigen-reactivity to peripheral T-cells.ConclusionsOur study demonstrated the feasibility of efficiently identifying both CD4+ and CD8+ neoantigen-specific T-cells in EOC. Autologous lymphocytes genetically engineered with tumor antigen-specific TCR can be used to generate cells for use in the personalized adoptive T-cell transfer immunotherapy.
Highlights
Epithelial ovarian cancer (EOC) is the deadliest gynecological cancer, with approximately 22,240 new cases and 14,070 deaths in the United States for 2018
We identified a total of 2096 somatic mutations from the 20 patients, including 1368 non-synonymous somatic mutations, and the number of genes with altered amino acid sequence ranged from 9 to 183 per patient (Fig. 1b)
The two IL27RA loss-of-function mutations were both identified from locally invasive tumor while the third IL27RA missense mutation
Summary
Epithelial ovarian cancer (EOC) is the deadliest gynecological cancer, with approximately 22,240 new cases and 14,070 deaths in the United States for 2018. Recent correlative clinical studies indicate that T-cell reactivity to neoantigens is an important determinant of response to immune checkpoint inhibitors and other immunotherapies [7], suggesting that efforts to precisely define immunogenic neoantigens either for vaccination [8, 9] or adoptive T-cell therapy (ACT) [10, 11] could potentially provide clinical benefit [12]. Efficient identification of neoantigen-specific T-cell responses in epithelial ovarian cancer (EOC) remains a challenge. Existing investigations of spontaneous T-cell response to tumor neoepitope in EOC have taken the approach of comprehensive screening all neoantigen candidates, with a validation rate of 0.5–2%
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