AUTHOR=Li Zuyin , Wang Rangrang , Qiu Chen , Cao Can , Zhang Jianming , Ge Jun , Shi Yuanping 

TITLE=Role of DTL in Hepatocellular Carcinoma and Its Impact on the Tumor Microenvironment

JOURNAL=Frontiers in Immunology

VOLUME=13

YEAR=2022

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2022.834606

DOI=10.3389/fimmu.2022.834606

ISSN=1664-3224

ABSTRACT=<sec><title>Background</title><p>The crucial role of <italic>DTL</italic> has been previously implicated in genomic stability; however, its prognostic value and its relation with tumor immunity in hepatocellular carcinoma (HCC) remain to be further explored.</p></sec><sec><title>Methods</title><p>Transcriptional and mutational datasets as well as clinical information were retrieved from the GEO, ICGC, and TCGA databases. Differentially expressed genes (DEGs) were obtained from the comparison of DTL<sup>high</sup> and DTL<sup>low</sup> expression groups of the TCGA-HCC cohort. Those genes were under KEGG and gene ontology (GO) analyses to decipher the influence of the DTL gene on the biological behavior of HCC tumor cells. The survival status and mutational characteristics of patients according to DTL levels were depicted and analyzed. The DTL overexpression in HCC and its impact on prognosis were further confirmed by a cohort of 114 HCC patients (validation cohort). The TIMER, GEPIA, and TISIDB databases were adopted to investigate the potential relations between DTL levels and the status of immune cells, as well as immune cell infiltrations.</p></sec><sec><title>Results</title><p>The <italic>DTL</italic> gene is overexpressed in tumor tissues compared with distant non-malignant liver tissues, and <italic>DTL</italic> overexpression in HCC would enhance the HCC cells in the activities of cell cycle and division. HCC patients with high <italic>DTL</italic> expression have unfavorable clinical outcomes and harbor more somatic mutations than those with low DTL expression, and multivariate analysis also revealed that <italic>DTL</italic> overexpression could act as an independent biomarker for prognosis. Moreover, the <italic>DTL</italic> gene was positively linked to marker sets of infiltrating activated CD8+ and CD4+ T cells; however, these cells demonstrated to be functionally exhausted.</p></sec><sec><title>Conclusions</title><p>Patients with a <italic>DTL</italic> overexpression phenotype in HCC have poorer prognosis than those in the DTL<sup>low</sup> group due to the role of the <italic>DTL</italic> gene in the process of pro-cell proliferation, accompanied by the immunosuppressive microenvironment and T cell exhaustion.</p></sec>