Role of CD47 gene expression in colorectal cancer: a comprehensive molecular profiling study

Background In patients with colorectal cancer (CRC), the therapeutic effects of conventional immune checkpoint inhibitors targeting the adaptive immune system are largely limited to those with microsatellite instability-high tumors. Meanwhile, new immunotherapies targeting the innate immune system are attracting increasing attention. CD47 is a representative innate immune checkpoint involved in the evasion of tumor cell phagocytosis by macrophages. This large-scale study comprehensively examined the molecular significance of CD47 gene expression in CRC. Methods We analyzed the next-generation sequencing data of DNA and RNA from 14,287 CRC cases included in the data set of a commercial Clinical Laboratory Improvement Amendments-certified laboratory (Caris Life Sciences). The cases were divided into two groups based on the median value of CD47 gene expression levels. The molecular and immune profiles between the groups were compared, and the relationship between CD47 expression and survival outcomes was further examined. Results In CD47-high tumors, the proportion of consensus molecular subtypes 1 and 4 was significantly higher than in CD47-low tumors. The expression levels of damage-associated molecular pattern-related genes showed a positive correlation with CD47 expression levels. Major oncogenic pathways, such as mitogen-activated protein kinase, phosphoinositide 3-kinase, angiogenesis, and transforming growth factor beta, were significantly activated in CD47-high tumors. Additionally, the expression levels of a panel of adaptive immune checkpoint genes and estimates of immune cells constituting the tumor microenvironment (TME) were significantly higher in CD47-high tumors. Conclusions CD47 expression in CRC was associated with the activation of several oncogenic pathways and an immune-engaged TME. Our findings may provide valuable information for considering new therapeutic strategies targeting innate immune checkpoints in CRC.