Mutational burden, immune checkpoint expression, and mismatch repair in glioma: implications for immune checkpoint immunotherapy
Mutational burden, immune checkpoint expression, and mismatch repair in glioma: implications for immune checkpoint immunotherapy
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DOI：
10.1093/neuonc/nox026
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发表时间：
2017-08-01
期刊：
影响因子：
15.9
通讯作者：
Heimberger, Amy B.
中科院分区：
文献类型：
--
作者：
Hodges, Tiffany R.;Ott, Martina;Heimberger, Amy B.
背景尽管有大量的临床试验测试免疫检查点抑制剂，潜在的预测生物标志物的表达频率在胶质瘤中是未知的。在这项研究中，我们分析了共享生物标志物表型的频率。为了阐明肿瘤突变负荷（TML），错配修复（MMR）和免疫检查点表达之间的关系，我们分析了胶质瘤患者（n = 327），包括胶质母细胞瘤（GBM）（n = 198），其样本已于2009年至2016年提交分析。TML的计算算法包括每个肿瘤的非同义突变计数，其中滤除种系突变。免疫组化分析和下一代测序用于确定肿瘤浸润淋巴细胞表达阳性的程序性细胞死亡蛋白1（PD-1）、肿瘤细胞上的PD配体1（PD-L1）表达、MMR（MLH 1、MSH 2、MSH 6和PMS 2）蛋白表达和突变以及DNA聚合酶抑制剂（POLE）突变。高TML仅见于3.5%的GBM患者（7/198），与mutL同源物1（MLH 1）蛋白表达缺失相关（P = .0345），mutS同源物2（MSH 2）（P = .0099），MSH 6（P = .0022），减数分裂后分离增加2（PMS 2）（P = .0345）和DNA MMR突变的存在。高和中等TML GBM不具有CD 8 + T细胞、PD-1+ T细胞或肿瘤表达的PD-L1的富集流入。IDH 1突变型胶质瘤不富含高TML、PD-1+ T细胞或PD-L1表达。为了阐明TML、MMR和免疫检查点表达之间的关系，我们分析了共享生物标志物表型的频率。基于对免疫检查点反应的各种潜在生物标志物，只有小部分胶质瘤患者可能受益于单药免疫检查点抑制。
Background. Despite a multiplicity of clinical trials testing immune checkpoint inhibitors, the frequency of expression of potential predictive biomarkers is unknown in glioma.Methods. In this study, we profiled the frequency of shared biomarker phenotypes. To clarify the relationships among tumor mutational load (TML), mismatch repair (MMR), and immune checkpoint expression, we profiled patients with glioma (n = 327), including glioblastoma (GBM) (n = 198), whose samples had been submitted for analysis from 2009 to 2016. The calculation algorithm for TML included nonsynonymous mutation counts per tumor, with germline mutations filtered out. Immunohistochemical analysis and next-generation sequencing were used to determine tumor-infiltrating lymphocyte expression positive for programmed cell death protein 1 (PD-1), PD ligand 1 (PD-L1) expression on tumor cells, MMR (MLH1, MSH2, MSH6, and PMS2) protein expression and mutations, and DNA polymerase epsilon (POLE) mutations.Results. High TML was only found in 3.5% of GBM patients (7 of 198) and was associated with the absence of protein expression of mutL homolog 1 (MLH1) (P = .0345), mutS homolog 2 (MSH2) (P = .0099), MSH6 (P = .0022), and postmeiotic segregation increased 2 (PMS2) (P = .0345) and the presence of DNA MMR mutations. High and moderate TML GBMs did not have an enriched influx of CD8+ T cells, PD-1+ T cells, or tumor-expressed PD-L1. IDH1 mutant gliomas were not enriched for high TML, PD-1+ T cells, or PD-L1 expression.Conclusions. To clarify the relationships among TML, MMR, and immune checkpoint expression, we profiled the frequency of shared biomarker phenotypes. On the basis of a variety of potential biomarkers of response to immune checkpoints, only small subsets of glioma patients are likely to benefit from monotherapy immune checkpoint inhibition.