Background The immunogenicity of the liver tumor microenvironment is clinically heterogeneous and mysterious. The insight into the role of immune cells including tumor-infiltrating lymphocytes (TILs) and chemokine networks, might enable optimal patient selection for immunotherapy. In this study, we aimed at characterizing the liver cancer immune subtypes linked to chemokines and associating with the patient characteristics and clinical outcomes.
Methods We analyzed the immune cells and chemokine signatures of human liver cancer using The Genotype-Tissue Expression (GTEx) and The Cancer Genome Atlas (TCGA) database profiling of 110 normal liver tissues and 369 liver tumor patients. We performed hierarchical clustering to the chemokine expression by applying immune cells status to categorize the CCL5-related chemokine in liver tumors. The separation was characterized by dividing the liver tumor patients into CCL5-high and low subtypes.
Results Our results showed that the high expression of myeloid-derived suppressor cells (MDSCs) is associated with a decrease in effector T cells expressing PRF1 in liver tumor progression. The chemokines and immune cells in CCL-5-high subtype including CCR5, MDSCs and effector T cells, are significantly associated with CCL5 and a potential predictive clinical benefit. The estimated odds for CCL5-low subtype liver tumors were higher than CCL5-high subtype liver tumors particularly in the stage IV tumors (OR = 3.54; 95 % CI: 0.36, 34.92). Our data demonstrated that the CCL5-high subtype significantly improved OS (p = 0.0379, hazard ratio 0.67; 95% CI 0.43, 0.98), DFI (p = 0.0104, hazard ratio 0.63; 95% CI 0.44, 0.90), PFI (p = 0.0066, hazard ratio 0.64; 95% CI 0.46, 0.89) and working performance status when compared to the CCL5-low subtype.
Conclusion Our findings provide a novel perspective of liver cancer chemokine subtypes linked to immune cells. A suitable therapy that can effectively activate effector T cells and inhibit MDSCs targeting chemokines might support the magnitude of lymphocytic infiltration in liver tumors, and should be considered for the design of precision therapies targeting the tumor and its immune microenvironment. The chemokine signatures in the CCL5-subtype are a valuable resource for future research to help identify clinically relevant biomarkers.