Key result
Predictive biomarkers such as tumor-infiltrating lymphocytes, PD-L1 expression, neoantigen load, and genetic signatures can help identify cancer patients likely to respond to immune checkpoint inhibitors.
Why the study?
Although CSF3 and CSF3R promote gastric cancer growth and metastasis, their effects on the immune microenvironment remain unclear.
Developing reliable predictive biomarkers such as immune cell profiling and neoantigen load is critical for selecting patients who will benefit from immune checkpoint inhibitors and avoiding immune-related adverse events.
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.
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Wang et al. (2025) conducted a review in Cancer. Immune checkpoint inhibitors was evaluated. Predictive biomarkers such as tumor-infiltrating lymphocytes, PD-L1 expression, neoantigen load, and genetic signatures can help identify cancer patients likely to respond to immune checkpoint inhibitors.
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