The CD8⁺T/MDSC ratio: A novel prognostic and predictive biomarker for immunotherapy response in gastric cancer

Background Immune imbalance in tumor microenvironment is closely linked to GC progression. MDSCs primarily drive immune imbalance by suppressing the anti-tumor activity of CD8⁺T cells. Notably, no prior study has explored the combination of CD8⁺T cells and MDSCs to assess the clinical prognosis or immunotherapy response in GC. Methods PubMed and EMBASE were searched, literature screened, and 5 eligible studies included for this first meta-analysis. Multiplex immunofluorescence detected the expression of CD11B, CD33, CD8, and PD-L1 in 236 GC patients. R software was used to construct the Nomogram model. Receiver operating characteristic curves, calibration curves, and decision curve analysis were applied to evaluate the accuracy, reliability, and clinical utility of the prediction model. In vitro and in vivo experiments explored the impact of MDSCs on the migration and invasion of GC cells. Multicolor flow cytometry measured the infiltration of CD8⁺T cells and MDSCs in the peripheral blood of patients with GC and GCLM. Single-cell RNA sequencing data and spatial transcriptomics data were compared to further validate the results. Results Meta-analysis showed high MDSC infiltration correlated with poor prognosis and advanced stage in GC patients. The AUC of the CD8⁺T/MDSC ratio for predicting OS in GC patients was significantly superior to that of CD8⁺T cells alone or MDSCs alone. A low CD8⁺T/MDSC ratio (≤ 5.38) was closely associated with lymph node metastasis and advanced TNM stage in GC patients. In vitro and in vivo experiments demonstrated MDSCs significantly enhanced the proliferation, migration, invasion, and liver metastatic capabilities of GC cells, while MDSC inhibitors reversed this pro-tumor effect. Multicolor flow cytometry indicated significantly increased MDSC infiltration and a decreased CD8⁺T/MDSC ratio in patients with liver metastasis, and scRNA-seq and spatial transcriptomics results corroborated these findings. Among GC patients treated with sintilimab, the therapeutic response rate was significantly higher in the high CD8⁺T/MDSC ratio group than in the low ratio group, establishing this ratio as the first reported composite immune biomarker for predicting sintilimab response in GC patients. Conclusions This is the first study to validate the CD8⁺T/MDSC ratio as a novel, reliable predictive biomarker for GC prognosis, metastasis, and immunotherapy response.