T-cell Responses to TP53 "Hotspot" Mutations and Unique Neoantigens Expressed by Human Ovarian Cancers.
T-cell Responses to TP53 "Hotspot" Mutations and Unique Neoantigens Expressed by Human Ovarian Cancers.
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DOI：
10.1158/1078-0432.ccr-18-0573
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发表时间：
2018-11-15
期刊：
影响因子：
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通讯作者：
Rosenberg SA
中科院分区：
文献类型：
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作者：
Deniger DC;Pasetto A;Robbins PF;Gartner JJ;Prickett TD;Paria BC;Malekzadeh P;Jia L;Yossef R;Langhan MM;Wunderlich JR;Danforth DN;Somerville RPT;Rosenberg SA
这是一项前瞻性评估肿瘤内T细胞对人转移性卵巢癌表达的自体体细胞突变新表位的应答的研究。从切除的卵巢癌转移瘤扩增肿瘤浸润性淋巴细胞（TIL），通过全外显子组和转录组测序对其进行分析以鉴定自体体细胞突变。所有突变的新表位，独立于预测算法，在自体抗原呈递细胞中表达，然后与TIL片段培养物共培养。干扰素-γ的分泌或41 BB的上调指示T细胞应答。评估了7名患有转移性卵巢癌的女性，5名患者对突变的新抗原具有明确的显性T细胞应答，这通过与野生型序列的比较、最小表位、人白细胞抗原（HLA）限制性元件和新抗原特异性T细胞受体的鉴定来证实。突变的新抗原受到HLA-B、-C、-DP、-DQ和/或-DR等位基因的限制，并且似乎主要由每个患者特有的随机体细胞突变产生。我们确定了由两个不同患者的肿瘤表达的TP 53“热点”突变（c.659A>G; p.Y220C和c.733G>A; p.G245S）在HLA-DRB 3 *02：02的情况下都是免疫原性的。突变反应性T细胞以足够的频率浸润卵巢癌转移，以保证其作为过继细胞治疗的研究。此外，将TP 53“热点”突变反应性T细胞受体转移到外周血T细胞中可以作为多种肿瘤组织学的基因治疗进行评估。
This was a study prospectively evaluating intratumoral T-cell responses to autologous somatic mutated neoepitopes expressed by human metastatic ovarian cancers. Tumor infiltrating lymphocytes (TILs) were expanded from resected ovarian cancer metastases, which were analyzed by whole exome and transcriptome sequencing to identify autologous somatic mutations. All mutated neoepitopes, independent of prediction algorithms, were expressed in autologous antigen presenting cells then co-cultured with TIL fragment cultures. Secretion of interferon-gamma or up-regulation of 41BB indicated a T-cell response. Seven women with metastatic ovarian cancer were evaluated and 5 patients had clear, dominant T-cell responses to mutated neoantigens, which were corroborated by comparison to the wild type sequence, identification of the minimal epitope, human leukocyte antigen (HLA) restriction element(s) and neoantigen-specific T-cell receptor(s). Mutated neoantigens were restricted by HLA-B, -C, -DP, -DQ and/or -DR alleles and appeared to principally arise from random, somatic mutations unique to each patient. We established that TP53 “hotspot” mutations (c.659A>G; p.Y220C and c.733G>A; p.G245S) expressed by two different patient’s tumors were immunogenic both in the context of HLA-DRB3*02:02. Mutation-reactive T cells infiltrated ovarian cancer metastases at sufficient frequencies to warrant their investigation as adoptive cell therapy. Additionally, transfer of TP53 “hotspot” mutation-reactive T-cell receptors into peripheral blood T cells could be evaluated as a gene therapy for a diverse range of tumor histologies.