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J Immunother Cancer. 2019 Jun 20;7(1):156. doi: 10.1186/s40425-019-0629-6.

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

Author information

1
Department of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, NY, 14263, USA. song.liu@roswellpark.org.
2
Center for Immunotherapy, Roswell Park Comprehensive Cancer Center, Buffalo, NY, 14263, USA. junko.matsuzaki@roswellpark.org.
3
Department of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, NY, 14263, USA.
4
Center for Immunotherapy, Roswell Park Comprehensive Cancer Center, Buffalo, NY, 14263, USA.
5
Gynecologic Cancer Center of Excellence, Department of Obstetrics and Gynecology, John P. Murtha Cancer Center, Uniformed Services University and Walter Reed National Military Medical Center, Bethesda, MD, 20889, USA.
6
Department of Gynecologic Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, 14263, USA.
7
Department of Cancer Prevention and Control, Roswell Park Comprehensive Cancer Center, Buffalo, NY, 14263, USA.
8
Department of Obstetrics and Gynecology, Inova Fairfax Medical Campus, Falls Church, VA, 22003, USA.
9
Inova Schar Cancer Institute, Falls Church, VA, 22003, USA.
10
Center for Immunotherapy, Roswell Park Comprehensive Cancer Center, Buffalo, NY, 14263, USA. kunle.odunsi@roswellpark.org.
11
Department of Gynecologic Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, 14263, USA. kunle.odunsi@roswellpark.org.

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.

KEYWORDS:

Anti-tumor effect; CD4+ T-cells; CD8+ T-cells; Gene therapy; Neoantigen; Ovarian cancer; T-cell receptor

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