Targeting the tumor mutanome for personalized vaccination in a TMB low non-small cell lung cancer.
Targeting the tumor mutanome for personalized vaccination in a TMB low non-small cell lung cancer.
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靶向肿瘤杂种组在TMB低的非小细胞肺癌中进行个性化疫苗接种。
DOI：
10.1136/jitc-2021-003821
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发表时间：
2022-03
影响因子：
10.9
通讯作者：
Ottensmeier C
中科院分区：
文献类型：
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作者：
McCann K;von Witzleben A;Thomas J;Wang C;Wood O;Singh D;Boukas K;Bendjama K;Silvestre N;Nielsen FC;Thomas G;Sanchez-Elsner T;Greenbaum J;Schoenberger S;Peters B;Vijayanand P;Savelyeva N;Ottensmeier C
癌症的特征是体细胞突变的积累，其中相当一部分可产生能被自体T细胞识别的癌症特异性新表位。这类新表位正成为癌症免疫疗法的重要靶点，包括个性化癌症疫苗接种策略。
我们利用全外显子组和RNA测序分析来确定一名非小细胞肺癌患者的潜在新抗原。此后，我们在培养的干扰素γ酶联免疫斑点试验中使用长肽方法评估了自体T细胞对候选新抗原的反应性，并通过T细胞受体（TCR）测序追踪肿瘤中的新抗原特异性T细胞。同时，将已识别的基因变异纳入一种基于改良痘苗病毒安卡拉株的疫苗中，并在人白细胞抗原A*0201转基因小鼠模型（HHD）中对该疫苗进行了评估。
测序显示肿瘤的突变负荷较低：从原发肿瘤中鉴定出2219个序列变异，其中23个在转录组中表达，涉及18种基因产物。我们能够证明对5/18（28%）的突变基因变异存在自发性T细胞反应，并且对新抗原特异性CD4⁺和CD8⁺T细胞的TCR库的进一步分析显示，TCR克隆型在血液和肿瘤组织中均有扩增。在对HHD小鼠接种疫苗后，对4/18（22%）的突变基因变异产生了新的T细胞反应；在自体环境中，针对两种变异有反应的T细胞也很明显。随后，我们确定了T细胞反应的主要组织相容性复合体限制，并使用计算机预测工具来确定可能的新表位。
我们的研究证明了在突变负荷较低的肿瘤中有效识别可通过疫苗接种靶向的肿瘤特异性新抗原的可行性，有望成功用于临床，相关试验目前正在进行中。
Cancer is characterized by an accumulation of somatic mutations, of which a significant subset can generate cancer-specific neoepitopes that are recognized by autologous T cells. Such neoepitopes are emerging as important targets for cancer immunotherapy, including personalized cancer vaccination strategies. We used whole-exome and RNA sequencing analysis to identify potential neoantigens for a patient with non-small cell lung cancer. Thereafter, we assessed the autologous T-cell reactivity to the candidate neoantigens using a long peptide approach in a cultured interferon gamma ELISpot and tracked the neoantigen-specific T-cells in the tumor by T-cell receptor (TCR) sequencing. In parallel, identified gene variants were incorporated into a Modified Vaccinia Ankara-based vaccine, which was evaluated in the human leucocyte antigen A*0201 transgenic mouse model (HHD). Sequencing revealed a tumor with a low mutational burden: 2219 sequence variants were identified from the primary tumor, of which 23 were expressed in the transcriptome, involving 18 gene products. We could demonstrate spontaneous T-cell responses to 5/18 (28%) mutated gene variants, and further analysis of the TCR repertoire of neoantigen-specific CD4+ and CD8+ T cells revealed TCR clonotypes that were expanded in both blood and tumor tissue. Following vaccination of HHD mice, de novo T-cell responses were generated to 4/18 (22%) mutated gene variants; T cells reactive against two variants were also evident in the autologous setting. Subsequently, we determined the major histocompatibility complex restriction of the T-cell responses and used in silico prediction tools to determine the likely neoepitopes. Our study demonstrates the feasibility of efficiently identifying tumor-specific neoantigens that can be targeted by vaccination in tumors with a low mutational burden, promising successful clinical exploitation, with trials currently underway.
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影响因子：
82.9
作者：
Gros A;Parkhurst MR;Tran E;Pasetto A;Robbins PF;Ilyas S;Prickett TD;Gartner JJ;Crystal JS;Roberts IM;Trebska-McGowan K;Wunderlich JR;Yang JC;Rosenberg SA
通讯作者：
Rosenberg SA
影响因子：
22.7
作者：
Han J;Zhao Y;Shirai K;Molodtsov A;Kolling FW;Fisher JL;Zhang P;Yan S;Searles TG;Bader JM;Gui J;Cheng C;Ernstoff MS;Turk MJ;Angeles CV
通讯作者：
Angeles CV
CD8+ T细胞和CD4+ T细胞的同时浸润是非小细胞肺癌中的一个有利的预后因素。
影响因子：
8.8
作者：
通讯作者：
--
影响因子：
4.6
作者：
Bankhead P;Loughrey MB;Fernández JA;Dombrowski Y;McArt DG;Dunne PD;McQuaid S;Gray RT;Murray LJ;Coleman HG;James JA;Salto-Tellez M;Hamilton PW
通讯作者：
Hamilton PW
影响因子：
4.8
作者：
Bendjama, Kaidre;Quemeneur, Eric
通讯作者：
Quemeneur, Eric