Therapeutic anti-tumor immunity directed against neo-epitopes by intratumor delivery of mRNA encoding MLKL.
02 Oct 2018-Vol. 2, Iss: 10, pp 279-281
TL;DR: Direct delivery in tumor cells of hypo-inflammatory messenger RNA that codes for mixed lineage kinase domain-like (MLKL) protein 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.
Abstract: 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.
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TL;DR: Wang et al. as mentioned in this paper found that P. aeruginosa infection resulted in tumor cell necrotic cell death and HMGB1 production, indicating that the infection can cause immunogenic cell death.
Abstract: Necroptosis is a form of programmed cell death (PCD) which is characterized by RIP3 mediated MLKL activation and increased membrane permeability via MLKL oligomerization. Tumor cell immunogenic cell death (ICD) has been considered to be essential for the anti-tumor response, which is associated with DC recruitment, activation, and maturation. In this study, we found that P. aeruginosa showed its potential to suppress tumor growth and enable long-lasting anti-tumor immunity in vivo. What’s more, phosphorylation- RIP3 and MLKL activation induced by P. aeruginosa infection resulted in tumor cell necrotic cell death and HMGB1 production, indicating that P. aeruginosa can cause immunogenic cell death. The necrotic cell death can further drive a robust anti-tumor response via promoting tumor cell death, inhibiting tumor cell proliferation, and modulating systemic immune responses and the local immune microenvironment in tumors. Moreover, dying tumor cells killed by P. aeruginosa can catalyze DC maturation, which enhanced the antigen-presenting ability of DC cells. These findings demonstrate that P. aeruginosa can induce immunogenic cell death and trigger a robust long-lasting anti-tumor response along with reshaping the tumor microenvironment.
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