AUTHOR=Tang Xi-Yang , Xiong Yan-Lu , Zhao Ya-Bo , Yang Jie , Shi An-Ping , Zheng Kai-Fu , Liu Yu-Jian , Shu Chen , Jiang Tao , Ma Nan , Zhao Jin-Bo 

TITLE=Dual immunological and proliferative regulation of immune checkpoint FGL1 in lung adenocarcinoma: The pivotal role of the YY1–FGL1–MYH9 axis

JOURNAL=Frontiers in Immunology

VOLUME=13

YEAR=2022

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2022.1014053

DOI=10.3389/fimmu.2022.1014053

ISSN=1664-3224

ABSTRACT=<sec><title>Rational</title><p>Lung cancer is the most common tumor worldwide, with the highest mortality rate and second highest incidence. Immunotherapy is one of the most important treatments for lung adenocarcinoma (LUAD); however, it has relatively low response rate and high incidence of adverse events. Herein, we explored the therapeutic potential of fibrinogen-like protein 1 (FGL1) for LUAD.</p></sec><sec><title>Methods</title><p>Data from GEPIA and ACLBI databases were assessed to explore gene–gene correlations and tumor immune infiltration patterns. A total of 200 patients with LUAD were recruited. FGL1 levels in the serum and cellular supernatant were determined by enzyme-linked immunosorbent assay. <italic>In vitro</italic> and <italic>in vivo</italic> experiments were performed to assess the effect FGL1 on the proliferation of LUAD cells. Cocultures were performed to explore the effect of FGL1 knockdown in lung cancer cells on T cells, concerning cytokine secretion and viability. PROMO and hTFtarget databases were used for transcription factor prediction. Quantitative polymerase chain reaction (qPCR), chromatin immunoprecipitation, and dual luciferase reporter assays were performed to validate the identified transcription factor of FGL1. Immunoprecipitation, mass spectrometry and gene ontology analysis were performed to explore the downstream partners of FGL1.</p></sec><sec><title>Results</title><p>FGL1 expression in LUAD was positively associated with <italic>PDL1</italic>, but not for <italic>PD1</italic> expression. Moreover, FGL1 was positively associated with the <italic>CD3D</italic> expression and negatively associated with <italic>FOXP3</italic>, <italic>S100A9</italic>, and <italic>TPSB2</italic> within the tumor site. FGL1 promotes the secretion of interleukin-2 by T cells <italic>in vitro</italic>, simultaneously inducing their apoptosis. Indeed, YY1 is the upstream molecule of FGL1 was found to be transcriptionally regulated by YY1 and to directly by to <italic>MYH9</italic> to promote the proliferation of LUAD cells <italic>in vitro</italic> and <italic>in vivo</italic>.</p></sec><sec><title>Conclusions</title><p>FGL1 is involved in the immunological and proliferative regulation of LUAD cells by controlling the secretion of important immune-related cytokines <italic>via</italic> the YY1–FGL1–MYH9 axis. Hence, targeting FGL1 in LUAD may pave the way for the development of new immunotherapies for tackling this malignancy.</p></sec>