Innate immune receptor C5aR1 regulates cancer cell fate and can be targeted to improve radiotherapy in tumours with immunosuppressive microenvironments

An immunosuppressive microenvironment causes poor tumor T cell infiltration and is associated with reduced patient overall survival in colorectal cancer. How to improve treatment responses in these tumors is still a challenge. Using an integrated screening approach to identify cancer-specific vulnerabilities, we identified complement receptor C5aR1 as a druggable target, which when inhibited improved radiotherapy, even in tumors displaying immunosuppressive features and poor CD8+ T cell infiltration. While C5aR1 is well-known for its role in the immune compartment, we found that C5aR1 is also robustly expressed on malignant epithelial cells, highlighting potential tumor cell-specific functions. C5aR1 targeting resulted in increased NF-κB-dependent apoptosis specifically in tumors and not normal tissues, indicating that, in malignant cells, C5aR1 primarily regulated cell fate. Collectively, these data revealed that increased complement gene expression is part of the stress response mounted by irradiated tumors and that targeting C5aR1 could improve radiotherapy, even in tumors displaying immunosuppressive features

A new method for assaying propantheline and its degradation product, xanthene-9- carboxylic acid using high performance liquid chromatography

A rapid, specific, and precise high-performance liquid chromatographic method is described for the simultaneous analysis of propantheline bromide and its hydrolysis product, xanthene-9-carboxylic acid. Reversed-phase chromatography was conducted using a mobile phase of 40:60, acetonitrile-0.05 M phosphate buffer (pH 2.5) delivered at 2 ml/min. Detection was at 254 nm. Methantheline bromide (internal standard), propantheline bromide, and xanthene-9-carboxylic acid gave retention times of 4.1, 5.4, and 8.3 min, respectively. Within-day, between-day, and total precision (CV) for assay of 15 mg/10 ml propantheline bromide are 1.2, 1.1, and 1.6%, respectively (n = 20). Similar precision was obtained for xanthene-9-carboxylic acid. The limit of detection was 2 ng. The assay is useful for routine quality assurance of propantheline in dosage forms and for stability and kinetic studies