人类白细胞抗原 (HLA) I 类表达的丧失和杂合性 (LOH) 的丧失是非小细胞肺癌 (NSCLC) 对免疫治疗的原发耐药性中涉及的常见事件。然而，尚无 HLA I 类缺陷背景下围手术期化学免疫治疗 (ChIO) 疗效或反应机制的数据。基线 HLA I 类肿瘤状态（HLA 缺陷 (HLA-DEF) 或 HLA 丰富 (HLA-PRO)）通过 DNA LOH 结合免疫组织化学测定了 NADIM 试验 (NCT03081689) 中接受围手术期纳武单抗联合化疗的 24 名 NSCLC 患者组织中的蛋白质水平。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 测序和空间转录组学 (ST)）和临床结果（病理反应和生存数据）相结合考虑 HLA I 类缺陷，研究围手术期 ChIO 的活性。HLA-DEF 肿瘤占分析肿瘤的 41.7%，在基线时显示出类似沙漠的微环境，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：无进展生存率 (PFS) HLA-DEF 的总生存 (OS) 为 70%（95% CI 32.9% 至 89.2%），PFS 为 71.4%（95% CI 40.6% 至 88.2%），OS 92.9%（95% CI 59.1% 至 99.0） %) 对于 HLA-PRO（对数秩 PFS p=0.909，OS p=0.137）。 ChIO 后 CPR HLA-DEF 肿瘤的概念验证 ST 分析显示，三级淋巴结构 (TLS)、具有 HLA II 类共定位的 CD4 T 细胞和激活的 CD8 T 细胞产生强烈的免疫反应。我们的研究结果强调了围手术期 ChIO，以及 TLS 和 T 细胞免疫反应在 NSCLC HLA-DEF 肿瘤中的潜在作用。© 作者（或其雇主）2024。在 CC BY-NC 下允许重复使用。禁止商业再利用。请参阅权利和权限。英国医学杂志出版。

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.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.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.Our findings highlight the activity of perioperative ChIO, and the potential role of TLS and T-cell immune response, in NSCLC HLA-DEF tumors.© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.