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Oxidation of Innate Immune Checkpoint CD47 on Cancer Cells with Non-Thermal Plasma
Abraham Lin1,2, Jamoliddin Razzokov1,3,4, Hanne Verswyvel1,2
1PLASMANT-Research Group, University of Antwerp, 2610 Antwerpen-Wilrijk, Belgium.
Abstract:
Non-thermal plasma (NTP) therapy has been emerging as a promising cancer treatment strategy, and recently, its ability to locally induce immunogenic cancer cell death is being unraveled. We hypothesized that the chemical species produced by NTP reduce immunosuppressive surface proteins and checkpoints that are overexpressed on cancerous cells. Here, 3D in vitro tumor models, an in vivo mouse model, and molecular dynamics simulations are used to investigate the effect of NTP on CD47, a key innate immune checkpoint. CD47 is immediately modulated after NTP treatment and simulations reveal the potential oxidized salt-bridges responsible for conformational changes. Umbrella sampling simulations of CD47 with its receptor, signal-regulatory protein alpha (SIRPα), demonstrate that the induced-conformational changes reduce its binding affinity. Taken together, this work provides new insight into fundamental, chemical NTP-cancer cell interaction mechanisms and a previously overlooked advantage of present NTP cancer therapy: reducing immunosuppressive signals on the surface of cancer cells.
Insights
Non-thermal plasma (NTP) therapy shows promise in cancer treatment by reducing immunosuppressive signals on cancer cells. NTP alters CD47, a key immune checkpoint, decreasing its binding affinity to SIRPα and potentially enhancing anti-tumor immunity.
Area of Science:
- Biomedical Engineering
- Cancer Immunology
- Plasma Medicine
Background:
- Non-thermal plasma (NTP) therapy is an emerging cancer treatment.
- NTP can induce immunogenic cancer cell death.
- The precise mechanisms of NTP's interaction with cancer cells, particularly regarding immune evasion, require further elucidation.
Purpose of the Study:
- To investigate the effect of NTP on CD47, an innate immune checkpoint protein.
- To understand how NTP-generated chemical species modulate CD47 expression and function.
- To explore the potential of NTP in overcoming cancer cell immune suppression.
Main Methods:
- Utilized 3D in vitro tumor models and an in vivo mouse model.
- Employed molecular dynamics simulations, including umbrella sampling, to study CD47-SIRPα interactions.
- Analyzed conformational changes and binding affinities after NTP treatment.
Main Results:
- NTP treatment rapidly modulated CD47 on cancer cells.
- Simulations identified potential oxidized salt-bridges causing CD47 conformational changes.
- These changes significantly reduced the binding affinity between CD47 and its receptor, signal-regulatory protein alpha (SIRPα).
Conclusions:
- NTP therapy can reduce immunosuppressive signals on cancer cell surfaces by targeting CD47.
- This modulation of CD47 represents a significant, previously unrecognized advantage of NTP cancer therapy.
- The findings provide fundamental insights into chemical NTP-cancer cell interactions and their immunomodulatory effects.
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