Tens of billions of cells are uneventfully eliminated from our bodies by apoptotic cell death each day. These cells do not elicit an immune response; indeed, apoptosis is generally considered to be immunologically tolerogenic. Many cancer therapies seek to trigger apoptotic death in tumor cells; one class of these drugs targets the cell surface Death Receptors (DRs). Recently however, we and others have demonstrated that under some conditions DR ligation can trigger another form of cell death termed necroptosis. Necroptosis is mechanistically and morphologically distinct from apoptosis; while the immune consequences of necroptosis are poorly understood, our preliminary data indicate that cells dying by necroptosis trigger inflammatory and immune responses. The description of necroptosis as a form of programmed cell death that is also immunogenic leads to our central hypothesis: That induction of necroptosis in tumors will promote beneficial anti-tumor immune responses that are prevented when tumor cells die by apoptosis. We will test this idea by pursuing two specific questions: 1. what is the effect of killing established tumors by necroptosis? And, 2. Can necroptosis promote tumor immunity? To address these questions, we have developed novel systems that allow us to rapidly and synchronously trigger either apoptosis or necroptosis in vivo using a non-toxic, cell permeable drug. We will use this novel system to directly assess the immune consequences of killing tumors via distinct cell death programs. This work represents the first assessment of the effects if killing tumors by inflammatory programmed cell death, and as such has the potential to identify novel and beneficial therapeutic targets.
Recent work has demonstrated that activation of different enzymes can lead to different types of cell death. These different cell death programs can have very different effects on the immune system. This project will test the effect of inducing immunogenic vs. non-immunogenic cell death in tumors.
| Orozco, Susana; Oberst, Andrew (2017) RIPK3 in cell death and inflammation: the good, the bad, and the ugly. Immunol Rev 277:102-112 |
| Gutierrez, Kimberley D; Davis, Michael A; Daniels, Brian P et al. (2017) MLKL Activation Triggers NLRP3-Mediated Processing and Release of IL-1? Independently of Gasdermin-D. J Immunol 198:2156-2164 |
| Oberst, Andrew (2016) Death in the fast lane: what's next for necroptosis? FEBS J 283:2616-25 |
| Rodriguez, D A; Weinlich, R; Brown, S et al. (2016) Characterization of RIPK3-mediated phosphorylation of the activation loop of MLKL during necroptosis. Cell Death Differ 23:76-88 |
| Yatim, Nader; Jusforgues-Saklani, Hélène; Orozco, Susana et al. (2015) RIPK1 and NF-?B signaling in dying cells determines cross-priming of CD8? T cells. Science 350:328-34 |
| Kang, Seokwon; Fernandes-Alnemri, Teresa; Rogers, Corey et al. (2015) Caspase-8 scaffolding function and MLKL regulate NLRP3 inflammasome activation downstream of TLR3. Nat Commun 6:7515 |
