围手术期化疗免疫治疗可诱导 HLA I 类缺陷的非小细胞肺癌患者产生强烈的免疫应答和长期生存。
Perioperative chemoimmunotherapy induces strong immune responses and long-term survival in patients with HLA class I-deficient non-small cell lung cancer.
机构信息
Departament of Medical Oncology, Hospital Universitario Puerta de Hierro Majadahonda, Majadahonda, Comunidad de Madrid, Spain.
Departamento de Bioquímica, Biología Molecular e Inmunología III. Instituto de Investigación Biosanitaria de Granada (Ibs. GRANADA), Universidad de Granada Facultad de Medicina, Granada, Andalucía, Spain.
出版信息
J Immunother Cancer. 2024 Oct 20;12(10):e009762. doi: 10.1136/jitc-2024-009762.
BACKGROUND
Loss of human leukocyte antigen (HLA) class I expression and loss of heterozygosity (LOH) are common events implicated in the primary resistance of non-small cell lung cancer (NSCLC) to immunotherapy. However, there is no data on perioperative chemoimmunotherapy (ChIO) efficacy or response mechanisms in the context of HLA class I defects.
METHODS
Baseline HLA class I tumor status (HLA-deficient (HLA-DEF) or HLA-proficient (HLA-PRO)) was determined by DNA LOH combined with immunohistochemistry for protein levels in tissue of 24 patients with NSCLC treated with perioperative nivolumab plus chemotherapy from NADIM trial (NCT03081689). We integrated HLA tumor status with molecular data (programmed death-ligand 1 (PD-L1), TMB, TCR repertoire, TILs populations, bulk RNA-seq, and spatial transcriptomics (ST)) and clinical outcomes (pathological response and survival data) to study the activity of perioperative ChIO considering HLA class I defects.
RESULTS
HLA-DEF tumors comprised 41.7% of analyzed tumors and showed a desert-like microenvironment at baseline, with lower PD-L1 levels and reduced immune infiltrate. However, perioperative ChIO induced similar complete pathological response (CPR) rates in both HLA-DEF and PRO tumors (50% and 60% respectively, p=0.670), as well as 3-year survival rates: Progression-free survival (PFS) and overall survival (OS) of 70% (95% CI 32.9% to 89.2%) for HLA-DEF, and PFS 71.4% (95% CI 40.6% to 88.2%) and OS 92.9% (95% CI 59.1% to 99.0%) for HLA-PRO (log-rank PFS p=0.909, OS p=0.137). Proof-of-concept ST analysis of a CPR HLA-DEF tumor after ChIO showed a strong immune response with tertiary lymphoid structures (TLS), CD4+T cells with HLA class II colocalization, and activated CD8+T cells.
CONCLUSIONS
Our findings highlight the activity of perioperative ChIO, and the potential role of TLS and T-cell immune response, in NSCLC HLA-DEF tumors.
背景
人类白细胞抗原（HLA）I 类表达缺失和杂合性丢失（LOH）是导致非小细胞肺癌（NSCLC）对免疫治疗产生原发性耐药的常见事件。然而，在 HLA I 类缺陷的情况下，关于围手术期化疗免疫治疗（ChIO）疗效或反应机制尚无数据。
方法
通过 DNA LOH 结合组织免疫组化检测 24 例接受 NADIM 试验（NCT03081689）中接受围手术期纳武利尤单抗联合化疗治疗的 NSCLC 患者的 HLA I 类肿瘤状态（HLA 缺失（HLA-DEF）或 HLA 正常（HLA-PRO））。我们将 HLA 肿瘤状态与分子数据（程序性死亡配体 1（PD-L1）、TMB、TCR 库、TIL 群体、批量 RNA-seq 和空间转录组学（ST））以及临床结局（病理缓解和生存数据）整合，以研究考虑 HLA I 类缺陷的围手术期 ChIO 的活性。
结果
分析的肿瘤中 HLA-DEF 肿瘤占 41.7%，基线时表现为沙漠样微环境，PD-L1 水平较低，免疫浸润减少。然而，围手术期 ChIO 在 HLA-DEF 和 PRO 肿瘤中诱导相似的完全病理缓解（CPR）率（分别为 50%和 60%，p=0.670），以及 3 年生存率：无进展生存期（PFS）和总生存期（OS）分别为 70%（95%CI 32.9%至 89.2%）的 HLA-DEF，以及 PFS 71.4%（95%CI 40.6%至 88.2%）和 OS 92.9%（95%CI 59.1%至 99.0%）的 HLA-PRO（对数秩 PFS p=0.909，OS p=0.137）。ChIO 后 HLA-DEF 肿瘤 CPR 的初步 ST 分析显示出强烈的免疫反应，具有三级淋巴结构（TLS）、HLA II 类共定位的 CD4+T 细胞和激活的 CD8+T 细胞。
结论
我们的研究结果强调了围手术期 ChIO 的活性，以及在 HLA-DEF NSCLC 肿瘤中 TLS 和 T 细胞免疫反应的潜在作用。
Zotero 插件