SUMMARY
Adrian T. Ting, Ph.D., studies the molecular mechanisms that determine cellular survival or demise, with the perspective that these basic mechanisms underlie a number of human diseases including infectious diseases, inflammatory disorders, autoimmunity, graft rejection and cancer.
Dr. Ting's lab studies primarily post-translational mechanisms that dictate cell survival versus death in response to tumor necrosis factor (TNF). Even though TNF was discovered over 40 years ago as a factor that can kill tumor cells, its utility as a cytotoxic agent against tumors has proved to be a failure. On the contrary, TNF induces a pro-survival response in most tumor cells. Therefore, TNF is capable of inducing two dichotomous cellular responses, and the default response in most primary and transformed cells to TNF is survival. This has posed a challenge to its potential use in anti-tumor therapy.
Furthermore, TNF-mediated cytotoxicity presumably evolved as an antimicrobial mechanism, but the physiologic role of this cytotoxic mechanism remains poorly understood. These challenges in understanding TNF-mediated cell death are due to the fact that while most cells have the machinery to undergo cell death, they do not die due to the presence of checkpoints that block the death-signaling machinery. Dr. Ting's lab made the discovery that there is an early checkpoint dependent on nondegradative ubiquitin that prevents the TNF signaling molecule RIPK1 from interacting with the death-signaling machinery. This checkpoint thus shunts the response to cell survival. If this early checkpoint is disrupted, cells undergo death orchestrated by RIPK1. The lab has termed this form of cell death ripoptocide, and in vivo, ripoptocide is highly inflammatory. This early checkpoint is post-translationally regulated by enzymes, which are prime targets for pharmacological modulation in several human diseases.
Focus areas
Ongoing studies in Dr. Ting's lab revolve around understanding the molecular regulation of this early ubiquitin-dependent checkpoint at the basic level and the role of this checkpoint in diseases at the translational level.
- Cell death signaling. The early checkpoint is post-translationally regulated by ubiquitin E3 ligases, deubiquitinases, kinases, phosphatases and proteases. These enzymes cross-regulate one another and this interaction is poorly understood. A thorough understanding of this regulation could provide multiple targets for potential manipulation in many different diseases.
- Infectious diseases. This checkpoint and TNF-mediated cytotoxicity evolved as an antimicrobial defense mechanism, but it's not clear which pathogens are controlled by this mechanism and whether pathogens are able to trigger or subvert this response. Pathogen-derived molecules are likely to target the various enzymes involved in the regulation of the early checkpoint. There is significant value in finding those pathogen-derived molecules and understanding how they intersect with the early checkpoint to regulate ripoptocide.
- Cancer. Tumor cells are highly resistant to ripoptocide due to a strongly fortified early cell death checkpoint, which is one explanation why TNF is ineffective as an anti-tumor agent. Dr. Ting's lab is investigating strategies to disable the early checkpoint as a way to sensitize tumors to TNF-mediated cytotoxicity for use in cancer immunotherapy.
- Transplant. Another clinical situation where the early checkpoint is critical is allogeneic organ transplants. Dr. Ting is exploring the hypothesis that defects in the early TNF cell death checkpoint, which sensitizes cells to ripoptocide, underlies allograft rejection, and therefore, blocking ripoptocide could prolong allograft survival. Pharmacological agents that inhibit ripoptocide may be useful in organ transplants.
Significance to patient care
In recent years, immunotherapy based on immune checkpoint blockade has revolutionized anti-cancer treatment. Despite this advance, immunotherapy is effective only in some cancers, and within those cancers, a large proportion of patients do not respond to immunotherapy. Therefore, new approaches to immunotherapy will likely be beneficial in anti-cancer therapy. Most immunotherapy approaches have relied on "revving up" lymphocytes to kill tumor cells, but less attention has been paid to sensitizing tumor cells to the killing mediated by these revved-up lymphocytes.
Dr. Ting's research focuses on how to sensitize tumor cells to cytotoxicity mediated by the cytokine TNF. Despite its name, TNF has proved to be largely ineffective in killing tumor cells. Observations from the Ting lab and others over the past decade have shown this to be due to the presence of a cell death checkpoint early in the TNF receptor signaling cascade. Disruption of this early cell death checkpoint in tumor cells led to cell death, and this could be a strategy that can be applied to anti-cancer therapy. This strategy adds another weapon to the armory of cytotoxic immune cells that are engaging tumor cells and could therefore extend the range of tumor cells that can be killed.
In many ways, the immunological issues associated with organ transplants are opposite to those associated with cancer. Cancer is a function of insufficient immune-mediated killing, and therefore the clinical goal is to enhance this killing. Conversely, organ rejection is a function of excessive immune-mediated killing, and the clinical solution lies in dampening that killing. Observations from an allograft transplant model suggest that sensitizing the graft to TNF-mediated cell death accelerates rejection, whereas inhibiting TNF-mediated cell death delays rejection. Therefore, fortifying the cell death checkpoint to inhibit TNF-mediated cell death may be a clinical strategy to prolong allograft survival.
Thus, research on the regulation of cell death has a strong translational impact on cancer immunotherapy and organ transplants.