Department of Health Sciences and Technology, Samsung Advanced Institute of Health Science and Technology, Sungkyunkwan University, Seoul, Republic of Korea; Samsung Genome Institute, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.
Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.
Ann Oncol. 2020 Jul;31(7):902-911. doi: 10.1016/j.annonc.2020.04.004. Epub 2020 Apr 19.
Immune checkpoint inhibitors (ICIs) have been shown to be beneficial for some patients with advanced non-small-cell lung cancer (NSCLC). However, the underlying mechanisms mediating the limited response to ICIs remain unclear.
We carried out whole-exome sequencing on 198 advanced NSCLC tumors that had been sampled before anti-programmed cell death 1 (anti-PD-1)/programmed death-ligand 1 (PD-L1) therapy. Detailed clinical characteristics were collected on these patients. We designed a new method to estimate human leukocyte antigen (HLA)-corrected tumor mutation burden (TMB), a modification which considers the loss of heterozygosity of HLA from conventional TMB. We carried out external validation of our findings utilizing 89 NSCLC samples and 110 melanoma samples from two independent cohorts of immunotherapy-treated patients.
Homology-dependent recombination deficiency was identified in 37 patients (18.7%) and was associated with longer progression-free survival (PFS; P = 0.049). Using the HLA-corrected TMB, non-responders to ICIs were identified, despite having a high TMB (top 25%). Ten patients (21.3% of the high TMB group) were reclassified from the high TMB group into the low TMB group. The objective response rate (ORR), PFS, and overall survival (OS) were all lower in these patients compared with those of the high TMB group (ORR: 20% versus 59%, P = 0.0363; PFS: hazard ratio = 2.91, P = 0.007; OS: hazard ratio = 3.43, P = 0.004). Multivariate analyses showed that high HLA-corrected TMB was associated with a significant survival advantage (hazard ratio = 0.44, P = 0.015), whereas high conventional TMB was not associated with a survival advantage (hazard ratio = 0.63, P = 0.118). Applying this approach to the independent cohorts of 89 NSCLC patients and 110 melanoma patients, TMB-based survival prediction was significantly improved.
HLA-corrected TMB can reconcile the observed disparity in relationships between TMB and ICI responses, and is of predictive and prognostic value for ICI therapies.
免疫检查点抑制剂（ICIs）已被证明对某些晚期非小细胞肺癌（NSCLC）患者有效。然而，介导对 ICI 有限反应的潜在机制仍不清楚。
我们对 198 例接受抗程序性细胞死亡 1（抗 PD-1）/程序性死亡配体 1（PD-L1）治疗前的晚期 NSCLC 肿瘤进行了全外显子组测序。收集了这些患者的详细临床特征。我们设计了一种新方法来估计人类白细胞抗原（HLA）校正的肿瘤突变负荷（TMB），这是一种从常规 TMB 中考虑 HLA 杂合性丢失的修正方法。我们利用来自两个独立免疫治疗患者队列的 89 例 NSCLC 样本和 110 例黑色素瘤样本对我们的发现进行了外部验证。
在 37 例患者（18.7%）中发现同源依赖性重组缺陷，与无进展生存期（PFS；P=0.049）延长相关。使用 HLA 校正的 TMB，尽管 TMB 较高（前 25%），但仍能识别出对 ICI 无反应的患者。10 例患者（高 TMB 组的 21.3%）从高 TMB 组重新分类为低 TMB 组。与高 TMB 组相比，这些患者的客观缓解率（ORR）、PFS 和总生存期（OS）均较低（ORR：20%对 59%，P=0.0363；PFS：风险比=2.91，P=0.007；OS：风险比=3.43，P=0.004）。多变量分析表明，高 HLA 校正的 TMB 与显著的生存优势相关（风险比=0.44，P=0.015），而高常规 TMB 与生存优势无关（风险比=0.63，P=0.118）。将该方法应用于 89 例 NSCLC 患者和 110 例黑色素瘤患者的独立队列，基于 TMB 的生存预测得到显著改善。
HLA 校正的 TMB 可以调和 TMB 与 ICI 反应之间观察到的差异，并且对 ICI 治疗具有预测和预后价值。
