Institute for Research in Immunology and Cancer (IRIC), University of Montreal, Montreal, QC H3T 1J4, Canada.
Department of Chemistry, University of Montreal, Montreal, QC H2V 0B3, Canada.
Curr Oncol. 2024 May 30;31(6):3099-3121. doi: 10.3390/curroncol31060236.
Epithelial ovarian cancer (EOC) has not significantly benefited from advances in immunotherapy, mainly because of the lack of well-defined actionable antigen targets. Using proteogenomic analyses of primary EOC tumors, we previously identified 91 aberrantly expressed tumor-specific antigens (TSAs) originating from unmutated genomic sequences. Most of these TSAs derive from non-exonic regions, and their expression results from cancer-specific epigenetic changes. The present study aimed to evaluate the immunogenicity of 48 TSAs selected according to two criteria: presentation by highly prevalent HLA allotypes and expression in a significant fraction of EOC tumors. Using targeted mass spectrometry analyses, we found that pulsing with synthetic TSA peptides leads to a high-level presentation on dendritic cells. TSA abundance correlated with the predicted binding affinity to the HLA allotype. We stimulated naïve CD8 T cells from healthy blood donors with TSA-pulsed dendritic cells and assessed their expansion with two assays: MHC-peptide tetramer staining and TCR Vβ CDR3 sequencing. We report that these TSAs can expand sizeable populations of CD8 T cells and, therefore, represent attractive targets for EOC immunotherapy.
上皮性卵巢癌 (EOC) 并未从免疫疗法的进步中显著获益,主要是因为缺乏明确的可操作性抗原靶点。我们之前通过对原发性 EOC 肿瘤的蛋白质基因组分析,鉴定出 91 种源自未突变基因组序列的异常表达的肿瘤特异性抗原 (TSA)。这些 TSA 大多数来自非外显子区域,其表达是由于癌症特异性的表观遗传变化。本研究旨在评估根据两个标准选择的 48 种 TSA 的免疫原性:高流行的 HLA 同种型的呈递和在大量 EOC 肿瘤中的表达。使用靶向质谱分析,我们发现合成 TSA 肽脉冲导致树突状细胞高水平呈递。TSA 丰度与预测与 HLA 同种型的结合亲和力相关。我们用 TSA 脉冲树突状细胞刺激来自健康献血者的幼稚 CD8 T 细胞,并通过两种测定法评估其扩增:MHC-肽四聚体染色和 TCR Vβ CDR3 测序。我们报告这些 TSA 可以扩增相当数量的 CD8 T 细胞,因此是 EOC 免疫治疗的有吸引力的靶标。
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