TY - JOUR
T1 - Multiomics analysis reveals distinct immunogenomic features of lung cancer with ground-glass opacity
AU - Chen, Kezhong
AU - Bai, Jing
AU - Reuben, Alexandre
AU - Zhao, Heng
AU - Kang, Guannan
AU - Zhang, Chunliu
AU - Qi, Qingyi
AU - Xu, Yaping
AU - Hubert, Shawna
AU - Chang, Lianpeng
AU - Guan, Yanfang
AU - Feng, Lin
AU - Zhang, Kai
AU - Zhang, Kaitai
AU - Yi, Xin
AU - Xia, Xuefeng
AU - Cheng, Shujun
AU - Yang, Fan
AU - Zhang, Jianjun
AU - Wang, Jun
N1 - Funding Information:
*These authors contributed equally to this work. ‡Co–senior authors. Supported by the National Natural Science Foundation of China (82072566 and 81602001 [K.C.]) and Peking University People’s Hospital Research and Development Funds (RS2019-01 [K.C.]). J.Z. was supported by a Khalifa Scholar Award, the National Cancer Institute of the National Institutes of Health Research Project (grant R01CA234629-01), the AACR–Johnson & Johnson Lung Cancer Innovation Science Grant (18-90-52-ZHAN), the MD Anderson Physician Scientist Program, the Sabin Family Foundation Award, and the Duncan Family Institute Cancer Prevention Research Seed Funding Program.
Funding Information:
Supported by the National Natural Science Foundation of China (82072566 and 81602001 [K.C.]) and Peking University People?s Hospital Research and Development Funds (RS2019-01 [K.C.]). J.Z. was supported by a Khalifa Scholar Award, the National Cancer Institute of the National Institutes of Health Research Project (grant R01CA234629-01), the AACR?Johnson & Johnson Lung Cancer Innovation Science Grant (18-90-52-ZHAN), the MD Anderson Physician Scientist Program, the Sabin Family Foundation Award, and the Duncan Family Institute Cancer Prevention Research Seed Funding Program. The authors thank Yun Wang and Yanyan Hou of Peking University People?s Hospital for assistance with sample collection and preservation.
Publisher Copyright:
Copyright © 2021 by the American Thoracic Society
PY - 2021/11/15
Y1 - 2021/11/15
N2 - 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 (NCT 03320044).
AB - 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 (NCT 03320044).
KW - Circulating tumor DNA
KW - Genomics
KW - Ground-glass opacity
KW - Immune infiltration
KW - T-cell repertoire
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U2 - 10.1164/RCCM.202101-0119OC
DO - 10.1164/RCCM.202101-0119OC
M3 - Article
C2 - 34473939
AN - SCOPUS:85120455970
SN - 1073-449X
VL - 204
SP - 1180
EP - 1191
JO - American journal of respiratory and critical care medicine
JF - American journal of respiratory and critical care medicine
IS - 10
ER -