HLA-I 进化分歧赋予未经治疗的晚期非小细胞肺癌对 PD-1 阻断联合化疗的反应。

HLA-I Evolutionary Divergence Confers Response to PD-1 Blockade plus Chemotherapy in Untreated Advanced Non-Small Cell Lung Cancer.

机构信息

Department of Medical Oncology, Shanghai Pulmonary Hospital and Thoracic Cancer Institute, Tongji University School of Medicine, Shanghai, China.

State Key Laboratory of Cell Biology, Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, Shanghai, China.

出版信息

Clin Cancer Res. 2023 Dec 1;29(23):4830-4843. doi: 10.1158/1078-0432.CCR-23-0604.

DOI:10.1158/1078-0432.CCR-23-0604

PMID:37449971

Abstract

PURPOSE

PD-1 blockade plus chemotherapy has become the new standard of care in patients with untreated advanced non-small cell lung cancer (NSCLC), whereas predictive biomarkers remain undetermined.

EXPERIMENTAL DESIGN

We integrated clinical, genomic, and survival data of 427 NSCLC patients treated with first-line PD-1 blockade plus chemotherapy or chemotherapy from two phase III trials (CameL and CameL-sq) and investigated the predictive and prognostic value of HLA class I evolutionary divergence (HED).

RESULTS

High HED could predict significantly improved objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) in those who received PD-1 blockade plus chemotherapy [in the CameL trial, ORR: 81.8% vs. 53.2%; P = 0.032; PFS: hazard ratio (HR), 0.47; P = 0.012; OS: HR, 0.40; P = 0.014; in the CameL-sq trial, ORR: 89.2% vs. 62.3%; P = 0.007; PFS: HR, 0.49; P = 0.005; OS: HR, 0.38; P = 0.002], but not chemotherapy. In multivariate analysis adjusted for PD-L1 expression and tumor mutation burden, high HED was independently associated with markedly better ORR, PFS, and OS in both trials. Moreover, the joint utility of HED and PD-L1 expression showed better performance than either alone in predicting treatment benefit from PD-1 blockade plus chemotherapy. Single-cell RNA sequencing of 58,977 cells collected from 11 patients revealed that tumors with high HED had improved antigen presentation and T cell-mediated antitumor immunity, indicating an inflamed tumor microenvironment phenotype.

CONCLUSIONS

These findings suggest that high HED could portend survival benefit in advanced NSCLC treated with first-line PD-1 blockade plus chemotherapy. See related commentary by Dimou, p. 4706.

摘要

目的

PD-1 阻断联合化疗已成为未经治疗的晚期非小细胞肺癌（NSCLC）患者的新标准治疗方法，而预测性生物标志物仍未确定。

实验设计

我们整合了来自两项 III 期试验（CameL 和 CameL-sq）的 427 名接受一线 PD-1 阻断联合化疗或化疗的 NSCLC 患者的临床、基因组和生存数据，并研究了 HLA Ⅰ类进化分歧（HED）的预测和预后价值。

结果

高 HED 可显著预测接受 PD-1 阻断联合化疗的患者的客观缓解率（ORR）、无进展生存期（PFS）和总生存期（OS）的改善[在 CameL 试验中，ORR：81.8% vs. 53.2%；P = 0.032；PFS：风险比（HR），0.47；P = 0.012；OS：HR，0.40；P = 0.014；在 CameL-sq 试验中，ORR：89.2% vs. 62.3%；P = 0.007；PFS：HR，0.49；P = 0.005；OS：HR，0.38；P = 0.002]，但对化疗无影响。在调整 PD-L1 表达和肿瘤突变负担的多变量分析中，高 HED 与两项试验中 ORR、PFS 和 OS 的显著改善独立相关。此外，HED 和 PD-L1 表达的联合效用在预测 PD-1 阻断联合化疗的治疗获益方面优于单独使用。对来自 11 名患者的 58977 个细胞进行单细胞 RNA 测序表明，HED 较高的肿瘤具有改善的抗原呈递和 T 细胞介导的抗肿瘤免疫，表明肿瘤微环境呈炎症表型。