Purpose: Mismatch repair deficient (dMMR) tumors have demonstrated favorable responses to immune checkpoint inhibition targeting PD-1. However, more in-depth identification of predictors of response could further refine patient selection for immunotherapy treatment. Experimental Design: We undertook integrated evaluation performed on samples collected from 28 of 42 patients enrolled on the NCI-MATCH arm Z1D trial that evaluated PD-1 inhibition treatment with nivolumab in patients with non-colorectal dMMR tumors. Genomic analyses were performed using next-generation sequencing (NGS), whole exome sequencing, and RNA sequencing and supplemented by multiplex immunofluorescence performed on tissue samples. Results: In this dMMR population, more extensive alterations of microsatellites as assessed by measures of NGS was associated with clinical benefit and tumor mutational burden. RNA sequencing further revealed associations between clinical benefit and immune infiltration index. Gene sets enriched in patients with clinical benefit included interferon signaling, antigen processing and PI3K-AKT-mTOR signaling, while hedgehog signaling was found to be enriched in subjects lacking clinical benefit. Conclusions: These genomic data highlight the importance of immune infiltration and antigen presentation in dMMR tumors that respond to immune checkpoint blockade. In addition, they suggest that, even within a dMMR population, NGS based measures of MSI could serve as biomarkers of immunotherapy response.

中文翻译：

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基于下一代测序的 MSI 评分预测纳武利尤单抗治疗错配修复缺陷肿瘤的益处：NCI-MATCH 组 Z1D 的随访


目的： 错配修复缺陷 （dMMR） 肿瘤对靶向 PD-1 的免疫检查点抑制表现出良好的反应。然而，更深入地确定反应的预测因子可以进一步改进免疫治疗的患者选择。实验设计：我们对从 NCI-MATCH 组 Z1D 试验中入组的 42 名患者中的 28 名患者的样本进行了综合评估，该试验评估了纳武利尤单抗对非结直肠 dMMR 肿瘤患者的 PD-1 抑制治疗。使用下一代测序 （NGS） 、全外显子组测序和 RNA 测序进行基因组分析，并辅以对组织样本进行的多重免疫荧光。结果： 在该 dMMR 人群中，通过 NGS 测量评估的微卫星更广泛的改变与临床获益和肿瘤突变负荷相关。RNA 测序进一步揭示了临床获益与免疫浸润指数之间的关联。在具有临床益处的患者中富集的基因集包括干扰素信号传导、抗原加工和 PI3K-AKT-mTOR 信号传导，而发现刺猬信号在缺乏临床益处的受试者中富集。结论： 这些基因组数据强调了免疫浸润和抗原呈递在对免疫检查点阻断有反应的 dMMR 肿瘤中的重要性。此外，他们还表明，即使在 dMMR 人群中，基于 NGS 的 MSI 测量也可以作为免疫治疗反应的生物标志物。