Transcription factor RUNX3 promotes CD8⁺ T cell recruitment by CCL3 and CCL20 in lung adenocarcinoma immune microenvironment

Abstract

Considering the existence of immune-desert in tumor microenvironment, the clinical efficacy of immunotherapy for lung adenocarcinoma is limited. This study aims to investigate the ability of transcription factors in regulating tumor immune microenvironment in lung adenocarcinoma. RNA-seq data were collected from the The Cancer Genome Atlas database. The relationships between transcription factors and immune infiltrates were assessed. Runtrelated transcription factor 3 (RUNX3)-associated immune pathways were investigated by the Kyoto Encyclopedia of Genes and Genomes, Gene Ontology, and Gene set enrichment analysis. Upregulated chemokines in the RUNX3overexpressed cell line were determined by quantitative real-time polymerase chain reaction, western blot, and enzyme-linked immunosorbent assay. These chemokines were further confirmed in RUNX3-downregulated cell lines.Immunochemistry was conducted to determine the expression of RUNX3, CCL3, CCL20, and the numbers of CD8 + T lymphocytes in human lung cancer tissues. Chemokine receptors in CD8 + T cells were explored by flow cytometry and immunofluorescence. T cell recruitment was investigated by transwell assay. After screening 406 transcription factors, RUNX3 was found strongly correlated T cells, cytotoxic lymphocytes, and CD8 + T cells. RUNX3 was associated with a variety of immunomodulators, including LAG3, CTLA-4, PD-1, and TIGIT. More importantly, RUNX3 was involved in immune-related pathways, especially immune cell migration-related pathways. Further investigation exhibited RUNX3 could upregulate CCL3 and CCL20 whose receptors

Prognostic Value and Immune Characteristics of RUNX Family in Human Cancers: A Pan-cancer Analysis

“…Previous studies have reported that members of the RUNX gene family have crucial roles in immune reaction and immune cell in ltration. For example, RUNX3 was shown to promote CD8 + T cell recruitment in the LUAD immune microenvironment [31]. To better understand the association between the RUNX gene family and immune cell in ltration, we investigated the relationships between the RUNX family and immune subtypes.…”

Waiting in the wings: RUNX3 reveals hidden depths of immune regulation with potential implications for inflammatory bowel disease

“…78 Song et al found that RUNX3 upregulated CCL3 and CCL20 (Table 3) and thus promoted CD8 + T cell recruitment. 78 Interestingly, the downregulation of RUNX3 reduced CCL3 and CCL20 expression and CD8 + T cell infiltration. 78 Li et al 76 uncovered the role of miR-301a in antitumor immunity.…”

“…Upregulation of CCR5 and CCR6 receptors occurred in CD8 + effector T cells 78 . Song et al found that RUNX3 upregulated CCL3 and CCL20 (Table 3) and thus promoted CD8 + T cell recruitment 78 . Interestingly, the downregulation of RUNX3 reduced CCL3 and CCL20 expression and CD8 + T cell infiltration 78 …”

“…As a regulator of T cell growth, Runx3 increased the amounts of CD8 + T cells that infiltrated tumour microenvironment and inhibited tumorigenesis 76,77 . Upregulation of CCR5 and CCR6 receptors occurred in CD8 + effector T cells 78 . Song et al found that RUNX3 upregulated CCL3 and CCL20 (Table 3) and thus promoted CD8 + T cell recruitment 78 .…”

Runx Transcription Factors in T Cells—What Is Beyond Thymic Development?

“…The Runx-CBFb complex binds to the Ccl5 enhancer and, together with the chromatin organizer SATB1, restrains the expression of Ccl5 (157). Positive regulation of CCL3 and CCL20 by RUNX3 contributes to the recruitment of CD8 T cells into the microenvironment of lung adenocarcinoma, supporting antitumor immunity (158).…”