Colony-stimulating factor 3 and its receptor promote leukocyte immunoglobulin-like receptor B2 expression and ligands in gastric cancer

Abstract

BACKGROUND

Colony-stimulating factor 3 (CSF3) and its receptor (CSF3R) are known to promote gastric cancer (GC) growth and metastasis. However, their effects on the immune microenvironment remain unclear. Our analysis indicated a potential link between CSF3R expression and the immunosuppressive receptor leukocyte immunoglobulin-like receptor B2 (LILRB2) in GC. We hypothesized that CSF3/CSF3R may regulate LILRB2 and its ligands, angiopoietin-like protein 2 (ANGPTL2) and human leukocyte antigen-G (HLA-G), contributing to immunosuppression.

AIM

To investigate the relationship between CSF3/CSF3R and LILRB2, as well as its ligands ANGPTL2 and HLA-G, in GC.

METHODS

Transcriptome sequencing data from The Cancer Genome Atlas were analyzed, stratifying patients by CSF3R expression. Differentially expressed genes and immune checkpoints were evaluated. Immunohistochemistry (IHC) was performed on GC tissues. Correlation analyses of CSF3R, LILRB2, ANGPTL2, and HLA-G were conducted using The Cancer Genome Atlas data and IHC results. GC cells were treated with CSF3, and expression levels of LILRB2, ANGPTL2, and HLA-G were measured by quantitative reverse transcriptase-polymerase chain reaction and western blotting.

RESULTS

Among 122 upregulated genes in high CSF3R expression groups, LILRB2 showed the most significant increase. IHC results indicated high expression of LILRB2 (63.0%), ANGPTL2 (56.5%), and HLA-G (73.9%) in GC tissues. Strong positive correlations existed between CSF3R and LILRB2, ANGPTL2, and HLA-G mRNA levels (P < 0.001). IHC confirmed positive correlations between CSF3R and LILRB2 (P < 0.001), and HLA-G (P = 0.010), but not ANGPTL2 (P > 0.05). CSF3 increased LILRB2, ANGPTL2, and HLA-G expression in GC cells. Heterogeneous nuclear ribonucleoprotein H1 modulation significantly altered their expression, impacting CSF3’s regulatory effects.

CONCLUSION

The CSF3/CSF3R pathway may contribute to immunosuppression in GC by upregulating LILRB2 and its ligands, with heterogeneous nuclear ribonucleoprotein H1 playing a regulatory role.

Keywords: Gastric cancer; Immunosuppressive receptor; Colony-stimulating factor 3; Colony-stimulating factor 3 receptor; Leukocyte immunoglobulin-like receptor B2; Angiopoietin-like protein 2; Human leukocyte antigen-G; Heterogeneous nuclear ribonucleoprotein H1

Core Tip: This study investigates the relationship between colony-stimulating factor 3 (CSF3)/colony-stimulating factor 3 receptor (CSF3R) and leukocyte immunoglobulin-like receptor B2, along with its ligands angiopoietin-like protein 2 and human leukocyte antigen-G, in gastric cancer (GC). High CSF3R expression correlates with increased levels of leukocyte immunoglobulin-like receptor B2, along with its ligands angiopoietin-like protein 2, and human leukocyte antigen-G in both transcriptomic data and immunohistochemical analysis. CSF3 upregulates these immune checkpoints in GC cells, with heterogeneous nuclear ribonucleoprotein H1 modulating this effect. These findings suggest that the CSF3/CSF3R pathway may play a role in promoting immunosuppression in GC.