Center for Systems and Computational Biology, Rutgers Cancer Institute of New Jersey, Rutgers University, New Brunswick, NJ.
Department of Physics and Astronomy, Rutgers University, Piscataway, NJ.
J Natl Cancer Inst. 2018 Mar 1;110(3):316-320. doi: 10.1093/jnci/djx213.
Response to immune checkpoint therapy can be associated with a high mutation burden, but other mechanisms are also likely to be important. We identified a patient with metastatic gastric cancer with meaningful clinical benefit from treatment with the anti-programmed death-ligand 1 (PD-L1) antibody avelumab. This tumor showed no evidence of high mutation burden or mismatch repair defect but was strongly positive for presence of Epstein-Barr virus (EBV) encoded RNA. Analysis of The Cancer Genome Atlas gastric cancer data (25 EBV+, 80 microsatellite-instable [MSI], 310 microsatellite-stable [MSS]) showed that EBV-positive tumors were MSS. Two-sided Wilcoxon rank-sum tests showed that: 1) EBV-positive tumors had low mutation burden (median = 2.07 vs 3.13 in log10 scale, P < 10-12) but stronger evidence of immune infiltration (median ImmuneScore 2212 vs 1295, P < 10-4; log2 fold-change of CD8A = 1.85, P < 10-6) compared with MSI tumors, and 2) EBV-positive tumors had higher expression of immune checkpoint pathway (PD-1, CTLA-4 pathway) genes in RNA-seq data (log2 fold-changes: PD-1 = 1.85, PD-L1 = 1.93, PD-L2 = 1.50, CTLA-4 = 1.31, CD80 = 0.89, CD86 = 1.31, P < 10-4 each), and higher lymphocytic infiltration by histology (median tumor-infiltrating lymphocyte score = 3 vs 2, P < .001) compared with MSS tumors. These data suggest that EBV-positive low-mutation burden gastric cancers are a subset of MSS gastric cancers that may respond to immune checkpoint therapy.
对免疫检查点治疗的反应可能与高突变负担有关，但其他机制也可能很重要。我们鉴定了一名转移性胃癌患者，该患者接受抗程序性死亡配体 1（PD-L1）抗体avelumab 治疗后获得了有意义的临床获益。该肿瘤无高突变负担或错配修复缺陷的证据，但 EBV 编码 RNA 呈强阳性。对癌症基因组图谱胃癌数据（25 例 EBV+，80 例微卫星不稳定[MSI]，310 例微卫星稳定[MSS]）的分析显示，EBV 阳性肿瘤为 MSS。双侧 Wilcoxon 秩和检验显示：1）EBV 阳性肿瘤的突变负担较低（中位数=2.07 对数 10 刻度，与 MSI 肿瘤相比，P<10-12；中位数免疫评分 2212 与 1295，P<10-4；CD8A 的对数 2 倍变化=1.85，P<10-6），并且 2）EBV 阳性肿瘤的 RNA-seq 数据中免疫检查点通路（PD-1、CTLA-4 通路）基因表达更高（对数 2 倍变化：PD-1=1.85，PD-L1=1.93，PD-L2=1.50，CTLA-4=1.31，CD80=0.89，CD86=1.31，P<10-4），组织学上淋巴细胞浸润更高（中位数肿瘤浸润淋巴细胞评分=3 与 2，P<0.001）与 MSS 肿瘤相比。这些数据表明，EBV 阳性低突变负担胃癌是 MSS 胃癌的一个亚组，可能对免疫检查点治疗有反应。
