The frequency of neoantigens per somatic mutation rather than overall mutational load or number of predicted neoantigens per se is a prognostic factor in ovarian clear cell carcinoma
The frequency of neoantigens per somatic mutation rather than overall mutational load or number of predicted neoantigens per se is a prognostic factor in ovarian clear cell carcinoma
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DOI：
10.1080/2162402x.2017.1338996
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发表时间：
2017-01-01
期刊：
影响因子：
7.2
通讯作者：
Kakimi, Kazuhiro
中科院分区：
文献类型：
--
作者：
Matsushita, Hirokazu;Hasegawa, Kosei;Kakimi, Kazuhiro
来源于肿瘤特异性体细胞突变的新抗原是抗肿瘤免疫应答的优良靶标。在卵巢透明细胞癌（OCCC）中，检查点阻断在一部分患者中产生持久的反应。为了解决为什么只有一些患者有反应的问题，我们首先使用外显子组测序和表达阵列数据研究了74例常规治疗的OCCC患者的新抗原负荷和免疫特征。错义突变的数量和肿瘤中评估的总预测新抗原均与临床结果无关。然而，每个错义突变的新抗原数量（“neoAg频率”）确实与临床结果相关。考克斯多变量回归分析表明，低neoAg频率与无进展生存期（PFS）增加相关，是OCCC PFS的独立预测因素（p = 0.032），尤其是在I-II期（p D 0.0045）。免疫相关基因（包括与效应记忆CD 8 T细胞相关的基因）主要在I-II期患者中neoAg频率较低的肿瘤中表达，表明表达新抗原的免疫原性亚克隆（免疫编辑）发生了CD 8 T细胞介导的消除。相反，我们观察到HLA-A、-B和-C表达减少，（分别为p = 0.036、p = 0.026和p = 0.030）以及CTLA-4、PD-1、Tim-3和LAG 3与CD 8A表达的比率增加。（分别为p = 0.0064、p = 0.017、p = 0.033和p = 0.0136）。因此，受约束的抗肿瘤免疫可能导致有限的免疫编辑和不良预后。我们的研究结果表明，OCCC中的neoAg频率是临床结果的独立预后因素，并可能成为基于免疫调节剂治疗的潜在候选生物标志物。
Neoantigens derived from tumor-specific somatic mutations are excellent targets for anti-tumor immune responses. In ovarian clear cell carcinoma (OCCC), checkpoint blockade yields durable responses in a subset of patients. To approach the question of why only some patients respond, we first investigated neoantigen loads and immune signatures using exome sequencing and expression array data for 74 OCCC patients treated conventionally. Neither the number of missense mutations nor total predicted neoantigens assessed in the tumor correlated with clinical outcomes. However, the number of neoantigens per missense mutation ("neoAg frequency") did correlate with clinical outcomes. Cox multivariate regression analysis demonstrated that low neoAg frequencies correlated with increased progression-free survival (PFS) and was an independent predictive factor for PFS in OCCC (p = 0.032), especially at stage I-II (p D 0.0045). Immunity-associated genes including those related to effector memory CD8 T cells were dominantly expressed in tumors with low neoAg frequencies in stage I-II patients, suggesting CD8 T cell-mediated elimination of immunogenic sub-clones expressing neoantigens (immunoediting) had occurred. In contrast, we observed decreased HLA-A, -B, and -C expression (p = 0.036, p = 0.026, and p = 0.030, respectively) as well as increased ratios of CTLA-4, PD-1, Tim-3, and LAG3 to CD8A expression (p = 0.0064, p = 0.017, p = 0.033 and p = 0.0136, respectively) in stage I-II tumors with high neoAg frequencies. Constrained anti-tumor immunity may thus result in limited immunoediting, and poor prognosis. Our results show that neoAg frequency in OCCC is an independent prognostic factor for clinical outcome and may become a potential candidate biomarker for immunomodulatory agentbased treatments.