Serum alpha-fetoprotein (AFP) is one of the most widely used clinical diagnostic and prognostic biomarkers for hepatocellular carcinoma (HCC). However, its potential role in guiding treatment strategies remains limited, largely because the tumor microenvironment of AFP-positive HCC has not been well characterized. We integrated multiple types of public transcriptomic data to systematically delineate the features of AFP-positive HCC and their relevance to immunotherapy. Specifically, we used single-cell RNA-seq datasets, bulk RNA-seq data, and spatial transcriptomic data from several independent public cohorts. We found that STMN1+ and AFP+ malignant cell subsets were enriched in AFP-positive tumor tissues, while CYP3A4+ malignant cells were enriched in AFP-negative HCC. Regarding the immune microenvironment, we focused on two key immune cell types: regulatory CD4+ T cells (Tregs) and dendritic cells (DCs). We found that both Tregs and CXCL10+ DCs (DCs with high CXCL10 expression) were elevated in AFP-positive HCC. Moreover, these two cell types showed a highly significant positive correlation across multiple datasets. Spatial transcriptomic analysis revealed their spatial proximity, suggesting that the interaction between CXCL10+ DCs and Tregs shaped the immunosuppressive environment in AFP-positive HCC. Analysis of single-cell and spatial transcriptome data from patients receiving immunotherapy showed that the increased composition and spatial proximity of these two cell types were associated with non-response to immunotherapy. Our study, based on the computation and analysis of public data, revealed that the interaction between CXCL10+ DCs and Tregs may serve as a crucial factor contributing to the formation of the immunosuppressive microenvironment of AFP-positive HCC. This not only enhances researchers' understanding of the AFP-positive HCC microenvironment but also provides a potential immunotherapy target for AFP-positive HCC.
Luo et al. (Thu,) studied this question.