CD40 transcriptomic expression patterns across malignancies: implications for clinical trials of CD40 agonists

Area of Science:

• Immunology
• Oncology
• Genomics

Background:

• CD40 is a T-cell co-stimulatory receptor crucial for next-generation immunotherapies.
• Understanding CD40's role in cancer requires analyzing its expression alongside immune markers.

Purpose of the Study:

• To conduct a pan-cancer transcriptome analysis of CD40, its ligand, and related immune markers.
• To evaluate the co-expression patterns of CD40 and immune markers.
• To assess the clinical outcomes associated with CD40 expression in various cancers.

Main Methods:

• Analyzed transcriptome data for CD40, CD40 ligand, and common immune checkpoints/co-stimulators (PD-1, PD-L1, PD-L2, CTLA-4, LAG-3, ICOS, CD27, CD28, OX40, GITR).
• Classified RNA expression as high (75-100th percentile), moderate (25-74th), or low (0-24th) using a reference of 735 solid tumors.
• Correlated CD40 expression with clinical outcomes in both UCSD and TCGA cohorts.

Main Results:

• High CD40 expression was observed in 22% of 514 patients, most frequently in liver/bile duct (42%), pancreatic (42%), and ovarian (40%) cancers.
• High CD40 and low-moderate CD40 ligand expression, favorable for CD40 agonist therapy, was most common in ovarian (33%) and pancreatic (24%) cancers.
• High CD40 expression correlated with high CD28 and GITR transcripts in both UCSD and TCGA cohorts. It also correlated with longer overall survival after immunotherapy initiation (P=0.04) but was not an independent predictive biomarker.

Conclusions:

• High CD40 expression is linked to specific cancers (liver/bile duct, pancreatic, ovarian) and immune markers (CD28, GITR).
• Co-expression patterns of immune markers in individual patients warrant further investigation.
• These findings support the development of CD40-based and other immunotherapies.