Two cases of intrahepatic cholangiocelluar carcinoma with high insertion-deletion ratios that achieved a complete response following chemotherapy combined with PD-1 blockade
Two cases of intrahepatic cholangiocelluar carcinoma with high insertion-deletion ratios that achieved a complete response following chemotherapy combined with PD-1 blockade
复制标题
高插入缺失率肝内胆管细胞癌化疗联合PD-1阻断后获得完全缓解2例
DOI：
10.1186/s40425-019-0596-y
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发表时间：
2019-05-07
影响因子：
10.9
通讯作者：
Lu, Shichun
中科院分区：
文献类型：
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作者：
Sui, Minghao;Li, Yu;Lu, Shichun
背景：插入-缺失突变可以产生更多与主要组织相容性复合体1高亲和力的肿瘤特异性新抗原。在黑色素瘤和肾癌中，高插入-缺失突变比率也与对程序性死亡-1(PD-1)检查点阻断的良好反应有关。然而，高Indel比率与肝内胆管细胞癌(ICC)免疫治疗反应之间的相关性尚不清楚。病例介绍：2例IIIb期肝内胆管细胞癌复发患者接受PD-1阻断联合化疗。经过7个月和4个月的化疗和PD-1阻断(分别为3个和15个周期，5个和6个周期)，磁共振成像和正电子发射断层扫描结合计算机断层扫描显示，两例患者的完全缓解(CR)分别持续了近16个月和13个月。全外显子组测序和免疫组织化学分析显示，两例患者都具有微卫星稳定性(MSS)和错配修复(MMR)能力，PD-L1表达较弱，肿瘤突变负荷(TMB)分别为2.95和7.09个突变/Mb。患者2具有已知的赋予免疫治疗敏感性的TP53和PTEN突变，以及免疫治疗耐药突变JAK2，而患者1没有已知的与免疫治疗反应相关的突变。然而，这两名患者的Indel比率(48%和66.87%)高于71名ICC患者的中位数12.77%。此外，与另外6例经PD-1阻断治疗或联合化疗后出现部分缓解、病情稳定或进展的ICC患者相比，PD-L1表达、TMB、MSI和MMR状态与2例CR患者相比无差异，而INDELS频率在CR患者中显著增加。结论：这2例患者提示INDELS可能是除PD-L1表达、TMB、MSI和dMMR之外的新的预测PD-1阻断反应的指标，值得进一步临床研究。
Background: Insertion-deletion mutations (indels) may generate more tumour-specific neoantigens with high affinity to major histocompatibility complex class 1. A high indel ratio is also related to a good response to programmed death-1 (PD-1) checkpoint blockade in melanoma and renal cell carcinoma. However, the correlation between a high indel ratio and the immunotherapy response in intrahepatic cholangiocarcinoma (ICC) is unknown.Case presentation: Two patients with relapsed ICC at stage IIIb were treated with PD-1 blockade combined with chemotherapy. After 7 and 4 months of chemotherapy and PD-1 blockade (3 and 15 cycles, and 5 and 6 cycles, respectively), magnetic resonance imaging and positron emission tomography with computed tomography imaging showed that both patients achieved a complete response (CR), which has lasted up to nearly 16 and 13 months to date, respectively. Whole-exome sequencing and immunohistochemistry analysis showed that both patients had cancers with microsatellite stability (MSS) and mismatch repair (MMR) proficiency, weak PD-L1 expression, and a tumour mutation burden (TMB) of 2.95 and 7.09 mutations/Mb, respectively. Patient 2 had mutations of TP53 and PTEN that are known to confer sensitivity to immunotherapy, and the immunotherapy-resistant mutation JAK2, whereas patient 1 had no known immunotherapy response-related mutations. However, the indel ratios of the two patients (48 and 66.87%) were higher than the median of 12.77% determined in a study of 71 ICC patients. Moreover, comparison to six additional ICC patients who showed a partial response, stable disease, or progressive disease after PD-1 blockade treatment alone or in combination with chemotherapy demonstrated no difference in PD-L1 expression, TMB, MSI, and MMR status from those of the two CR patients, whereas the indel frequency was significantly higher in the CR patients.Conclusions: These two cases suggest that indels might be a new predictor of PD-1 blockade response for ICC patients beside PD-L1 expression, TMB, MSI, and dMMR, warranting further clinical investigation.