Efficient identification of neoantigen-specific T-cell responses in advanced human ovarian cancer

• Main Authors: Song Liu, Junko Matsuzaki, Lei Wei, Takemasa Tsuji, Sebastiano Battaglia, Qiang Hu, Eduardo Cortes, Laiping Wong, Li Yan, Mark Long, Anthony Miliotto, Nicholas W. Bateman, Shashikant B. Lele, Thinle Chodon, Richard C. Koya, Song Yao, Qianqian Zhu, Thomas P. Conrads, Jianmin Wang, George L. Maxwell, Amit A. Lugade, Kunle Odunsi
• Format: Article
• Language: English
• Published: BMJ Publishing Group 2019-06-01
• Series: Journal for ImmunoTherapy of Cancer
• Subjects: Neoantigen; Ovarian cancer; CD4+ T-cells; CD8+ T-cells; Anti-tumor effect; T-cell receptor
• Online Access: http://link.springer.com/article/10.1186/s40425-019-0629-6

Abstract Background 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%. Methods Whole-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. Results Using 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. Conclusions Our 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.