Target profiling in bulk and single-cell RNA-seq expression data reveals differential co-expression patterns by data type

Siglec-15 is a novel target for immunotherapy in cancer and exhibits low mRNA expression in normal tissues but broad expression across cancer indications, specifically on tumor-associated macrophages and tumor cells. Expression of Siglec-15 and the immune checkpoint molecule PD-L1 have previously been reported to be mutually exclusive.

In a large-scale meta-analysis of bulk and single-cell RNA-seq data, we showed that co-expression of Siglec-15 and PD-L1 varied across indications.

Notably, while the targets showed a positive correlation in several indications in bulk RNA-seq data, a different pattern emerged at the single cell level: In 30 single cell studies spanning over 1.3 million cells, only a small fraction of cells were found to co-express Siglec-15 and PD-L1 on the same cell. The majority of the cells co-expressing the genes were macrophages.

Key Findings

This study demonstrated that at the bulk tumor level, Siglec-15 and PD-L1 mRNA expression are not broadly mutually exclusive across cancer indications, contrary to the published literature. In fact, their expression is mostly positively correlated, and their expression is mutually exclusive only at the individual cell level.