Cancer Cell:晚期肾癌抗PD-1反应和耐药性的决定因素

2021-11-23 “生物世界”公众号 “生物世界”公众号

该研究揭示了ccRCC抗PD-1反应和耐药性的特点,鉴定出了具有细胞毒性特征的肿瘤特异性T细胞,为该癌症过继细胞治疗的发展带来了希望。

肾透明细胞癌(ccRCC)是肾癌最常见的类型,占肾癌的70%-80%,且全球范围内发病率在不断上升。ccRCC是免疫浸润最严重的实体瘤类型之一,与其他癌症相比,高免疫浸润与肾切除术后不良预后相关。对Atezolizumab(抗PD-L1单抗,T药)和Nivolumab(抗PD-1单抗,O药)治疗产生应答的患者中,淋巴细胞系的占比明显要高很多。然而,这些特征作为预测性生物标志物的交叉验证产生了不一致的结果。

近日,英国弗朗西斯·克里克研究所、伦敦大学学院癌症研究所的研究团队联合在 Cancer Cell 上发表了题为:Determinants of anti-PD-1 response and resistance in clear cell renal cell carcinoma 的研究论文。

ADAPTeR(NCT02446860)是一项关于Nivolumab治疗转移性ccRCC患者的II期单臂开放标签研究,在基线、第9周、手术时和疾病进展时,对患者的原发和/或转移部位进行多区域肿瘤取样。ADAPTeR的主要目的是评估整个治疗过程中的分子和肿瘤免疫微环境(TME)特征。

通过ADAPTeR队列,研究团队发现Nivolumab治疗前应答者中扩增的TCR克隆数量显着增加,治疗后维持高度相似的TCR簇可预测反应,Nivolumab结合的CD8+T细胞被扩增并表达GZMK/B,表明Nivolumab促进了先前扩增的T细胞克隆的维持和替换,但只有维持与应答相关,因此维持和增强预先存在的反应是抗PD-1作用模式的关键因素。

首先,研究团队进行了全外显子组和RNA测序(RNA-seq)。他们发现,有10个人内源逆转录病毒(HERV)基因和12个长末端重复序列(LTR)元件将应答者与无应答者区分开来。重要的是,几乎所有这些基因都主要在治疗前无应答者中表达,表明HERV和对ccRCC具有高度特异性的LTR元件在无反应者治疗前过度表达,并且与抗肿瘤免疫反应和抗PD-1反应缺陷有关。

进一步分析显示,与无应答者相比,来自应答者的肿瘤在治疗前和治疗后具有显着更高水平的T细胞,并且CD3E、CD8A 、GZMB和TCF7的表达也更高。“免疫激活”和“TCR 信号”通路在应答者中富集,但在无应答者中没有。

在任何时间点,研究团队观察到应答者之间的T细胞数量或PD-1总表达没有差异。治疗前应答者和无应答者的GZMB表达水平均较低。然而,治疗后(第9周),总体和CD8+T细胞特异性GZMB表达均显着增加。

免疫检查点抑制剂激活的肿瘤特异性T细胞是否存在于肿瘤中,或是否被TME招募的新T细胞克隆所替代的问题仍在争论中。研究团队对14例患者治疗前后的β链TCR序列进行了排序,包括64例肿瘤和29例外周血单核细胞(PBMC)样本。总的来说,与PBMC相比,肿瘤样本中的TCR克隆性更高。应答者的基线肿瘤内TCR克隆性高于无应答者,但治疗后差异不显着。反应了先前扩增的TCR克隆的维持支持对应答者中预先存在的T细胞进行持续的抗原驱动刺激,以及Nivolumab结合预先扩增的CD8 + T细胞并在应答者中诱导细胞毒性表型。

综上,该研究揭示了ccRCC抗PD-1反应和耐药性的特点,鉴定出了具有细胞毒性特征的肿瘤特异性T细胞,为该癌症过继细胞治疗的发展带来了希望,同时,多组学分析流程为ccRCC未来的免疫肿瘤生物标志物研究提供了重要参考。

 

原始出处:

Lewis Au, et al. Determinants of anti-PD-1 response and resistance in clear cell renal cell carcinoma. Cancer Cell, 2021.

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    2021-12-14 维他命
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