Therapeutic anti-tumor immunity directed against neo-epitopes by intratumor delivery of mRNA encoding MLKL

In recent years, it has become increasingly clear that successful treatment of cancer is possible through the induction of anti-tumor immunity combined with killing of tumor cells. One approach to reach this is to apply cancer vaccines comprising tumor-specific antigens to elicit cellular immunity and chemotherapy to reduce the tumor mass. However, in some cases the dying tumor cell can itself become the vaccine, in particular when the antineoplastic treatment induces so called immunogenic cell death. Immunogenic cell death is characterized by the exposure of damage associated molecular patterns (DAMPs). DAMPs are recognized by innate immune cells which subsequently can prime effector T cell responses against tumor-specific antigens. Unfortunately, many tumors resist exogenous immunogenic cell death stimuli through acquired mutations in cell death signaling pathways. In our recent study (Nat Commun, 9(1):3417), we aimed to overcome these issues through the direct delivery in tumor cells of hypo-inflammatory messenger RNA (mRNA) that codes for mixed lineage kinase domain-like (MLKL) protein, an executioner of necroptosis. This mRNA-based treatment resulted in the potent induction of systemic cellular anti-tumor immune responses that were associated with the regression of the treated as well as distal non-treated tumor cells, as demonstrated in mouse models of transplantable tumors.