Cancer cells dying from ferroptosis impede dendritic cell-mediated anti-tumor immunity

Immunogenic cell death significantly contributes to the success of anti-cancer therapies, but immunogenicity of different cell death modalities widely varies. Ferroptosis, a form of cell death that is characterized by iron accumulation and lipid peroxidation, has not yet been fully evaluated from this perspective. Here we present an inducible model of ferroptosis, distinguishing three phases in the process-'initial' associated with lipid peroxidation, 'intermediate' correlated with ATP release and 'terminal' recognized by HMGB1 release and loss of plasma membrane integrity-that serves as tool to study immune cell responses to ferroptotic cancer cells. Co-culturing ferroptotic cancer cells with dendritic cells (DC), reveals that 'initial' ferroptotic cells decrease maturation of DC, are poorly engulfed, and dampen antigen cross-presentation. DC loaded with ferroptotic, in contrast to necroptotic, cancer cells fail to protect against tumor growth. Adding ferroptotic cancer cells to immunogenic apoptotic cells dramatically reduces their prophylactic vaccination potential. Our study thus shows that ferroptosis negatively impacts antigen presenting cells and hence the adaptive immune response, which might hinder therapeutic applications of ferroptosis induction. Inducing ferroptosis of tumour cells is a promising therapeutic approach in cancer. Authors show here that on the other hand, cells dying via ferroptosis are less immunogenic than necroptotic cells, they inhibit maturation and antigen cross-presentation of dendritic cells, hence lessen the anti-tumour immune response.

Automated summary

Ferroptosis, a form of cell death characterized by iron accumulation and lipid peroxidation, has lower immunogenicity compared to other cell death modalities, inhibiting the maturation and antigen cross-presentation of immune cells and hence weakening the anti-tumor immune response.