Rationale: Ground-glass opacity (GGO)-associated lung cancers are common and radiologically distinct clinical entities known to have an indolent clinical course and superior survival, implying a unique underlying biology. However, the molecular and immune characteristics of GGO-associated lung nodules have not been systemically studied. Objectives: To provide mechanistic insights for the treatment of these radiologically distinct clinical entities. Methods: We initiated a prospective cohort study to collect and characterize pulmonary nodules with GGO components (nonsolid and part-solid nodules) or without GGO components, as precisely quantified by using three-dimensional image reconstruction to delineate the molecular and immune features associated with GGO. Multiomics assessment conducted by using targeted gene panel sequencing, RNA sequencing, TCR (T-cell receptor) sequencing, and circulating tumor DNA detection was performed. Measurements and Main Results: GGO-associated lung cancers exhibited a lower tumor mutation burden than solid nodules. Transcriptomic analysis revealed a less active immune environment in GGO components and immune pathways, decreased expression of immune activation markers, and less infiltration of most immune-cell subsets, which was confirmed by using multiplex immunofluorescence. Furthermore, T-cell repertoire sequencing revealed lower T-cell expansion in GGO-associated lung cancers. HLA loss of heterozygosity was significantly less common in lung adenocarcinomas with GGO components than in those without. Circulating tumor DNA analysis suggested that the release of tumor DNA to the peripheral blood was correlated with the tumor size of non-GGO components. Conclusions: Compared with lung cancers presenting with solid lung nodules, GGO-associated lung cancers are characterized by a less active metabolism and a less active immune microenvironment, which may be the mechanisms underlying their indolent clinical course. Clinical trial registered with www.clinicaltrials.gov (NCT03320044).

中文翻译：

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多组学分析揭示了具有磨玻璃影的肺癌的独特免疫基因组学特征。

基本原理：磨玻璃影 (GGO) 相关肺癌是常见且放射学上不同的临床实体，已知具有惰性临床病程和优越的生存率，这意味着独特的潜在生物学。然而，尚未系统地研究 GGO 相关肺结节的分子和免疫特征。目标：为治疗这些放射学上不同的临床实体提供机制见解。方法：我们发起了一项前瞻性队列研究，以收集和表征具有 GGO 成分（非实性和部分实性结节）或不具有 GGO 成分的肺结节，通过使用三维图像重建精确量化以描述与 GGO 相关的分子和免疫特征. 通过使用靶向基因面板测序、RNA 测序进行的多组学评估，进行了 TCR（T 细胞受体）测序和循环肿瘤 DNA 检测。测量和主要结果：GGO 相关肺癌表现出比实性结节更低的肿瘤突变负荷。转录组学分析显示 GGO 成分和免疫通路中的免疫环境不太活跃，免疫激活标记物的表达减少，大多数免疫细胞亚群的浸润较少，这通过多重免疫荧光得到证实。此外，T 细胞库测序显示 GGO 相关肺癌中的 T 细胞扩增较低。HLA 杂合性丢失在具有 GGO 成分的肺腺癌中明显低于不具有 GGO 成分的肺腺癌。循环肿瘤 DNA 分析表明，肿瘤 DNA 向外周血的释放与非 GGO 成分的肿瘤大小相关。结论：与以实性肺结节为表现的肺癌相比，GGO 相关肺癌具有代谢活性较低和免疫微环境活性较低的特征，这可能是其惰性临床过程的潜在机制。在 www.clinicaltrials.gov (NCT03320044) 注册的临床试验。