AUTHOR=Wang Qinyang , Mao Ziyang , Li Wenyuan , Wang Shumei , Wang Lei , Chen Lin , Yang Zhe , Fu Xiaolan , Jiang Panpan , Bai Yixue , Xu Longwen , Zhang Shirong , Hou Yuzhu , Jia Xiaohui , Jiang Lili , Liu Mengjie , Zhang Guanjun , Jiang Yina , Guo Hui 

TITLE=Characteristics of the immunogenicity and tumor immune microenvironment in HER2-amplified lung adenocarcinoma

JOURNAL=Frontiers in Immunology

VOLUME=13

YEAR=2022

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2022.1042072

DOI=10.3389/fimmu.2022.1042072

ISSN=1664-3224

ABSTRACT=<sec><title>Objective</title><p>Besides breast and gastric cancer, <italic>HER2</italic> amplification/mutation are also found in lung adenocarcinoma (LUAD). However, the correlation between <italic>HER2</italic> variations and the phenotype of immunogenicity and tumor immune microenvironment (TIME) in LUAD compared with breast and gastric cancer has yet to be fully elucidated.</p></sec><sec><title>Methods</title><p>We integrated public databases (discovery set) and internal data (validated set) of 288 patients representing three distinct <italic>HER2</italic>-altered tumors. Genomic data were used to identify somatic mutations, copy number variations, and calculate tumor mutational burden (TMB) and microsatellite instability score. RNA sequencing was conducted to estimate immune gene signatures and contents of tumor-infiltrating immune cell populations. Finally, IHC was used to determine PD-L1 expression and the tumoral-infiltration of immune cells in 50 <italic>HER2</italic>-variant tumor specimens with no prior therapeutic regimens.</p></sec><sec><title>Results</title><p>Compared with <italic>HER2</italic>-amplified breast and gastric cancers, patients with <italic>HER2</italic>-amplified LUAD showed higher immunogenicity, mainly manifested in immune checkpoints expression and tissue/blood TMB. Additionally, <italic>HER2</italic>-amplified LUAD exhibited an inflamed TIME with remarkably increased genes encoding HLAs, T-cell activity and immune cell-type, and accompanied with tumor‐infiltrating lymphocytes. In LUAD, patients with <italic>HER2</italic> amplification possessed higher tissue TMB than <italic>HER2</italic> mutation, whereas no difference was observed in PD-L1 expression. <italic>HER2</italic> amplification (primary) was associated with significantly higher PD-L1 expression and TMB than acquired <italic>HER2</italic> amplification after resistance to EGFR-TKIs.</p></sec><sec><title>Conclusion</title><p>Patients with <italic>HER2</italic>-amplified LUAD have better immunogenicity and/or an inflamed TIME among <italic>HER2</italic>-aberrant tumors. Our study may provide clues for establishing the benefits and uses of ICIs for patients with this disease.</p></sec>