Neoantigens present unique and specific targets for personalized cancer immunotherapy strategies. Given the low mutational burden yet immunotherapy responsiveness of malignant mesothelioma (MM) when compared to other carcinogen-induced malignancies, identifying candidate neoantigens and T cells that recognize them has been a challenge. We used pleural effusions to gain access to MM tumor cells as well as immune cells in order to characterize the tumor-immune interface in MM. We characterized the landscape of potential neoantigens from SNVs identified in 27 MM patients and performed whole transcriptome sequencing of cell populations from 18 patient-matched pleural effusions. IFNγ ELISpot was performed to detect a CD8+ T cell responses to predicted neoantigens in one patient. We detected a median of 68 (range 7-258) predicted neoantigens across the samples. Wild-type non-binding to mutant binding predicted neoantigens increased risk of death in a model adjusting for age, sex, smoking status, histology and treatment (HR: 33.22, CI: 2.55-433.02, p = .007). Gene expression analysis indicated a dynamic immune environment within the pleural effusions. TCR clonotypes increased with predicted neoantigen burden. A strong activated CD8+ T-cell response was identified for a predicted neoantigen produced by a spontaneous mutation in the ROBO3 gene. Despite the challenges associated with the identification of bonafide neoantigens, there is growing evidence that these molecular changes can provide an actionable target for personalized therapeutics in difficult to treat cancers. Our findings support the existence of candidate neoantigens in MM despite the low mutation burden of the tumor, and may present improved treatment opportunities for patients.

中文翻译：

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鉴定恶性间皮瘤中对预测的新抗原的 CD8+ T 细胞反应。

新抗原为个性化癌症免疫治疗策略提供了独特而具体的靶点。鉴于与其他致癌物诱导的恶性肿瘤相比，恶性间皮瘤 (MM) 的低突变负担和免疫治疗反应性，识别候选新抗原和识别它们的 T 细胞一直是一个挑战。我们使用胸腔积液来获取 MM 肿瘤细胞和免疫细胞，以表征 MM 中的肿瘤-免疫界面。我们对 27 名 MM 患者中鉴定的 SNV 的潜在新抗原进行了描述，并对 18 名患者匹配的胸腔积液中的细胞群进行了全转录组测序。进行 IFNγ ELISpot 以检测一名患者的 CD8+ T 细胞对预测的新抗原的反应。我们在样本中检测到中位数为 68（范围 7-258）的预测新抗原。野生型不与突变体结合预测新抗原在调整年龄、性别、吸烟状况、组织学和治疗的模型中会增加死亡风险（HR：33.22，CI：2.55-433.02，p = .007）。基因表达分析表明胸腔积液中存在动态免疫环境。TCR 克隆型随着预测的新抗原负荷而增加。对于由 ROBO3 基因自发突变产生的预测新抗原，鉴定出强烈的活化 CD8+ T 细胞反应。尽管与识别真正的新抗原相关的挑战，越来越多的证据表明，这些分子变化可以为难以治疗的癌症的个性化治疗提供可行的目标。