Reducing sialylation in melanoma increases classical pathway-mediated complement activation

Summary Based on the success in pre-clinical models, methods that reduce sialylation in tumors have progressed to clinical trials, as this improves anti-tumor cellular responses. Immune responses against cancer can also be mediated by soluble, non-cellular mechanisms, such as the complement system. Dysregulation of the complement cascade and hypersialylation are hallmarks found across tumor types. Sialic acids are known to interact with complement proteins. However, the downstream pathways involved in the regulation of the complement cascade when reducing sialylation in tumors remain unclear. Here, using human melanoma cell lines and patient samples, we show that metabolic or enzymatic targeting of sialylation directly increases the activation of the complement, enhancing C3 opsonization of tumor cells and the formation of the membrane attack complex. This is mediated by the classical pathway of the complement system, in line with increased binding of immunoglobulins to tumor cells when sialylation is impaired. Our work positions the complement cascade as a relevant anti-tumor response playing a role when sialylation is targeted for cancer treatment. Graphical abstract