Role of necroptotic cancer cells in anti-cancer immunity

Abstract Successful immunogenic apoptosis in experimental cancer therapy depends on the induction of strong host anti-tumor responses. Given that tumors are often resistant to apoptosis, it is important to identify alternative molecular mechanisms that elicit immunogenic cell death. Necroptosis is one form of regulated necrosis and is mediated by RIPK1, RIPK3, and its substrate mixed lineage kinase domain-like and has been reported to contribute to inflammation under pathological conditions. Necroptosis is commonly induced by ligand-dependent activation of certain members of the TNFR and TLR families. To circumvent the use of cell death-inducing ligands or other immune active molecules that would not allow us to evaluate the immune response resulting uniquely from necroptosis induction, we opted for the use of inducible Tet-On systems for the expression of the downstream necroptotic effector proteins, allowing us to induce necroptosis independently of any receptor activation. In our genetic model a direct dimerization of FADD combined with inducible expression of RIPK3 promotes necroptosis. We report that necroptotic cancer cells release DAMPs and promote maturation of dendritic cells, the cross-priming of cytotoxic T cells, and the production of IFN-γ in response to tumor antigen stimulation. Using both FADD-dependent and FADD-independent RIPK3 induction systems, we demonstrate the efficient vaccination potential of immunogenic necroptotic cells. Our study broadens the current concept of immunogenic cell death and opens doors for the development of new strategies in cancer therapy.