抗原加工和呈递机制的基因特征可预测非小细胞肺癌 (NSCLC) 和黑色素瘤对检查点阻断的反应。

Gene signature of antigen processing and presentation machinery predicts response to checkpoint blockade in non-small cell lung cancer (NSCLC) and melanoma.

机构信息

Pulmonary and Critical Care, Thoracic Oncology Group, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA

Hematology/Oncology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA.

出版信息

J Immunother Cancer. 2020 Oct;8(2). doi: 10.1136/jitc-2020-000974.

BACKGROUND

Limited data exist on the role of alterations in HLA Class I antigen processing and presentation machinery in mediating response to immune checkpoint blockade (ICB).

METHODS

This retrospective cohort study analyzed transcriptional profiles from pre-treatment tumor samples of 51 chemotherapy-refractory advanced non-small cell lung cancer (NSCLC) patients and two independent melanoma cohorts treated with ICB. An antigen processing machinery (APM) score was generated utilizing eight genes associated with APM ( and ). Associations were made for therapeutic response, progression-free survival (PFS) and overall survival (OS).

RESULTS

In NSCLC, the APM score was significantly higher in responders compared with non-responders (p=0.0001). An APM score above the median value for the cohort was associated with improved PFS (HR 0.34 (0.18 to 0.64), p=0.001) and OS (HR 0.44 (0.23 to 0.83), p=0.006). The APM score was correlated with an inflammation score based on the established T-cell-inflamed resistance gene expression profile (Pearson's r=0.58, p<0.0001). However, the APM score better predicted response to ICB relative to the inflammation score with area under a receiving operating characteristics curve of 0.84 and 0.70 for PFS and OS, respectively. In a cohort of 14 high-risk resectable stage III/IV melanoma patients treated with neoadjuvant anti-PD1 ICB, a higher APM score was associated with improved disease-free survival (HR: 0.08 (0.01 to 0.50), p=0.0065). In an additional independent melanoma cohort of 27 metastatic patients treated with ICB, a higher APM score was associated with improved OS (HR 0.29 (0.09 to 0.89), p=0.044).

CONCLUSION

Our data demonstrate that defects in antigen presentation may be an important feature in predicting outcomes to ICB in both lung cancer and melanoma.

背景

关于 HLA Ⅰ类抗原加工和呈递机制的改变在介导免疫检查点阻断（ICB）反应中的作用，目前数据有限。

方法

本回顾性队列研究分析了 51 例化疗耐药的晚期非小细胞肺癌（NSCLC）患者和 2 例接受 ICB 治疗的独立黑色素瘤队列患者治疗前肿瘤样本的转录谱。利用与抗原加工机制（APM）相关的 8 个基因（和）生成 APM 评分。对治疗反应、无进展生存期（PFS）和总生存期（OS）进行了相关性分析。

结果

在 NSCLC 中，应答者的 APM 评分明显高于无应答者（p=0.0001）。队列中 APM 评分中位数以上与改善的 PFS（HR 0.34（0.18 至 0.64），p=0.001）和 OS（HR 0.44（0.23 至 0.83），p=0.006）相关。APM 评分与基于已建立的 T 细胞浸润抵抗基因表达谱的炎症评分相关（Pearson r=0.58，p<0.0001）。然而，APM 评分与 ICB 反应的相关性优于炎症评分，其 PFS 和 OS 的接收者操作特征曲线下面积分别为 0.84 和 0.70。在接受新辅助抗 PD1 ICB 的 14 例高危可切除 III/IV 期黑色素瘤患者队列中，较高的 APM 评分与改善的无病生存期相关（HR：0.08（0.01 至 0.50），p=0.0065）。在另一项接受 ICB 治疗的 27 例转移性黑色素瘤患者的独立队列中，较高的 APM 评分与改善的 OS 相关（HR 0.29（0.09 至 0.89），p=0.044）。