Identification of CEACAM5 as a stemness-related inhibitory immune checkpoint in pancreatic cancer.

ABSTRACT

BACKGROUND: Immunotherapy has emerged as a new cancer treatment modality. However, tumour heterogeneity can diminish checkpoint blockade response and shorten patient survival. As a source of tumour heterogeneity, cancer stem cells act as an indispensable reservoir for local recurrence and distant metastasis. Thus, precision immunotherapy targeting tumour heterogeneity requires a comprehensive understanding of cancer stem cell immunology. Our study aimed to identify stemness-related inhibitory immune checkpoints and relevant regulatory pathways in pancreatic cancer. METHODS: Pancreatic cancer-specific datasets in The Cancer Genome Atlas and the Cancer Therapeutics Response Portal were collected for in-depth bioinformatic analysis. Differentially expressed genes between pancreatic cancers with high and low stemness index (mRNAsi) scores were compared to screen out inhibitory immune checkpoints. Survival analysis was used to predict the prognostic value of immune checkpoint plus immune infiltrate in patients with pancreatic cancer. The expression of stemness-related immune checkpoint across immune subtypes of pancreatic cancer was detected and gene set enrichment analysis was performed to figure out the relevant regulatory signallings. RESULTS: The abundance of cancer stemness predicted a low immunotherapy response to pancreatic cancer. The inhibitory immune checkpoint CEACAM5 that was enriched in pancreatic cancers with high mRNAsi scores also exhibited a strong correlation with invasive cell-enriched signature and Msi+ tumour-initiating cell-enriched signature. Levels of CEACAM5 expression were higher in the interferon-γ dominant immune subtype of pancreatic cancers that are characterized by high M1 macrophage infiltration. The patient group with high levels of CEACAM5 expression had a high risk of poor overall survival, even if accompanied by high infiltration of M1 macrophages. Furthermore, prostanoid and long-chain unsaturated fatty acid metabolic processes showed a significant association with cancer stemness and CEACAM5 expression. CONCLUSIONS: Our findings suggest that CEACAM5 is a candidate stemness-related innate immune checkpoint in pancreatic cancer, and is potentially regulated by prostanoid and long-chain unsaturated fatty acid metabolic processes. Immune checkpoint blockade of CEACAM5, which synergizes with inhibition of those regulatory pathways, may improve the efficacy of precision immunotherapy targeting tumour heterogeneity caused by cancer stem cells.