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

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. Electronic supplementary material The online version of this article (10.1186/s40425-019-0629-6) contains supplementary material, which is available to authorized users.

Neoantigen vaccine: an emerging tumor immunotherapy

“…After the incorporation of tumor infiltrating lymphocytes (TILs) containing~25% neoantigen-specific auxiliary Th1 cells into tumor tissues, the target lesions of the patients reduced, and the stable time of the disease was prolonged, leading to significant tumor regression. In the current study, Song et al [128] sequenced whole exome and transcriptomes in patients with epithelial ovarian cancer (EOC) to identify neoantigen candidates and then analyzed the reactions of neoantigen-specific CD4+ and CD8+ T cell response in tumor or the peripheral blood. The specific T cell receptors (TCR) were transferred to peripheral blood T cells, making them with a neoantigen reactivity.…”

Adoptive Cell Therapy—Harnessing Antigen-Specific T Cells to Target Solid Tumours

“…Neoantigen-specific T cells can be identified in patients not only with melanoma, but also with epithelial cancers, such as lung cancer [119,120], gastrointestinal cancer [121][122][123], ovarian cancer [124][125][126], breast cancer [127] and pancreatic cancer [128]. Case reports have demonstrated that treatment of the gastrointestinal and breast cancer patients with a T cell population highly enriched in neoepitope-specific T cells caused tumour regression [121,123,127].…”

Fidelity of human ovarian cancer patient-derived xenografts in a partially humanized mouse model for preclinical testing of immunotherapies

“…Combinatorial PD1 and CTLA4 blockade with adoptively transferred autologous PBMCs inhibit OVC growth in vivo in NSG mouse models We previously demonstrated that PBMCs and TILs/ TALs from OVC patients harbor tumor-recognizing T cells, and have efficacy toward autologous tumors. [25][26][27][28] We asked whether adoptive transfer of OVC patientderived autologous PBMCs or autologous TILs/TALs in combination with ICB can control OVC growth in NSG mice. The general scheme of tumor implantation, ACT, IL2 treatment and checkpoint blockade schedules are depicted in figure 4A.…”