Early but not late ferroptotic cancer cells are immunogenic in vitro and in vivo

Cell-based immunotherapies hold great promise for the future treatment of cancer. The success of these therapies demonstrated the power of harnessing the immune system to eradicate tumors. It is also becoming clear that the 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 patients1. Since tumors often develop resistance to apoptosis and necroptosis, triggering these processes is not always the optimal strategy2. That is why it is crucial to find alternative ways to kill cancer cells and to select the proper immunogenic cell death type that is able to induce potent and strong anti-cancer immune responses, potentially leading to tumor eradication. Ferroptosis, an iron-dependent form of cell death leading to lipid peroxidation in cells, is currently actively studied3. We reported that cancer cells undergoing ferroptosis are immunogenic in vitro and in vivo4. Only early (not late) ferroptotic cells stimulate the phenotypic maturation of BMDCs and induce a vaccination-like effect in a tumor prophylactic vaccination model in immune-competent mice but not in immune-compromised Rag-2-/- mice. In addition, ATP and HMGB1, the best-characterized damage-associated molecular patterns that are involved in immunogenic cell death, have proven to be passively released along the timeline of ferroptosis and act as an immunogenic signal associated with the immunogenicity of early ferroptotic cancer cells. Altogether, these results identify early ferroptotic cancer cells as effective inducers of an adaptive immune response, and induction of ferroptosis in cancer might be another option to overcome cell death resistance and enhance the efficacy of anti-cancer therapy. 1. Galluzzi, L. et al.(2017) Nat. Rev. Immunol. 17, 97–111 2. Krysko, O. et al.(2017) Immunol. Rev. 280, 207–219 3. Friedmann Angeli, J. P. et al.(2019) Nat. Rev. Cancer 19, 405–414 4. Efimova, I. et al.(2020) J. Immunother. cancer 8, 1–15

Jaar van publicatie:2021