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Multiomics Analysis Reveals Distinct Immunogenomic Features of Lung Cancer with Ground-Glass Opacity

Authors: Chen, Kezhong; Bai, Jing; Reuben, Alexandre; Zhao, Heng; Kang, Guannan; Zhang, Chunliu; Qi, Qingyi; Xu, Yaping; Hubert, Shawna; Chang, Lianpeng; Guan, Yanfang; Feng, Lin; Zhang, Kai; Zhang, Kaitai; Yi, Xin; Xia, Xuefeng; Cheng, Shujun; Yang, Fan; Zhang, Jianjun; Wang, Jun

Online: https://www.atsjournals.org/doi/abs/10.1164/rccm.202101-0119OC

Issue: Am J Respir Crit Care Med. 2021 Nov 15;204(10):1180-1192.


Rationale: Ground-glass opacity (GGO)-associated lung cancers are common and radiologically distinct clinical entities known to have 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 Providing 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 (non-solid and part-solid) or without GGO components precisely quantified by 3D image reconstruction to delineate molecular and immune features associated with GGO. Multiomics assessment by targeted gene panel sequencing, RNA sequencing, T cell receptor sequencing and circulating tumor DNA detection was performed. Measurements and Main Results: GGO-associated lung cancers exhibited lower tumor mutation burden than solid nodules. Transcriptomic analysis revealed a less active immune environment in GGO and immune pathways, decreased expression of immune activation markers and lower infiltration of most immune cell subsets, which was confirmed by multiplex immunofluorescence. Furthermore, T cell repertoire (TCR) sequencing revealed lower T cell expansion in GGO-associated lung cancers. Loss of heterozygosity of HLA was significantly less common in lung adenocarcinomas with GGO components than those without. Circulating tumor DNA analysis suggested that release of tumor DNA to peripheral blood was correlated with tumor size of non-GGO components. Conclusions Compared to lung cancers presenting with solid lung nodules, GGO-associated lung cancers are characterized by less active metabolism and immune microenvironment that may be the mechanisms underlying their indolent clinical course.