Cell death stage dictates the immunogenicity of ferroptotic cancer cells

Immunotherapies hold great promise for the future treatment of cancer. It is also becoming clear that type of cancer cell death determines the antitumor immune response and, therefore, contributes to the efficiency of anti-cancer therapy and long-term survival of patients. Since tumors often develop resistance to apoptosis and necroptosis, triggering these processes is not always the optimal strategy. That is why it is crucial to select the proper cell death type potentially leading to tumor eradication. Ferroptosis, an iron-dependent form of cell death leading to lipid peroxidation in cells, is currently actively studied but whether ferroptotic cancer cells are immunogenic is unknown. We demonstrate for the first time that ferroptosis is immunogenic in vitro and in vivo. Early, but not late, ferroptotic cells promote the phenotypic maturation of BMDCs and elicit a vaccination-like effect in immune-competent mice but not in Rag-2−/− mice, suggesting that the mechanism of immunogenicity is very tightly regulated by the adaptive immune system and is time dependent. Also, ATP and HMGB1, the best-characterized damage-associated molecular patterns involved in immunogenic cell death, have proven to be passively released along the timeline of ferroptosis and act as immunogenic signal associated with the immunogenicity of early ferroptotic cancer cells. The work on approaches to increase the immunogenicity of late ferroptotic cells is underway, which will open up novel ferroptotic cell-based experimental strategies for cancer immunotherapy. In conclusion, these results indicate that induction of ferroptosis in cancer might be another option to overcome cell death resistance and enhance the efficacy of anti-cancer therapy.

Publication year:2021

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