6.4 Immunogenic cell death induced by plasma
8 min read•august 21, 2024
Plasma-induced immunogenic cell death is a cutting-edge approach in cancer therapy. It combines the direct killing of cancer cells with the activation of the immune system, offering unique advantages over traditional treatments.
This technique harnesses the power of plasma to generate reactive species and physical factors that trigger cell death. By releasing specific molecular signals, it stimulates a robust immune response against tumors, potentially leading to long-lasting anti-cancer effects.
Fundamentals of immunogenic cell death
- Immunogenic cell death plays a crucial role in plasma medicine by triggering immune responses against cancer cells
- Understanding the mechanisms of immunogenic cell death helps develop more effective plasma-based cancer treatments
- Plasma-induced immunogenic cell death offers unique advantages over traditional methods in cancer therapy
Definition and characteristics
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- Programmed cell death that stimulates an immune response against dying cells
- Characterized by the release of damage-associated molecular patterns (DAMPs)
- Involves exposure of calreticulin on the cell surface
- Triggers the release of ATP and HMGB1 from dying cells
- Differs from and in its immunostimulatory effects
Role in immune response
- Activates dendritic cells to present antigens from dying cells
- Stimulates T cell priming and activation against tumor-specific antigens
- Enhances the adaptive immune response against cancer cells
- Promotes long-term immunological memory against tumor antigens
- Overcomes immune tolerance mechanisms in the tumor microenvironment
Mechanisms of initiation
- Induced by various stressors (oxidative stress, ER stress, DNA damage)
- Requires the coordinated release of DAMPs in a specific temporal sequence
- Involves the activation of danger signaling pathways (TLR4, P2X7 receptors)
- Triggers the unfolded protein response in the endoplasmic reticulum
- Leads to the translocation of calreticulin from the ER to the cell surface
Plasma-induced immunogenic cell death
- Plasma treatment offers a unique approach to induce immunogenic cell death in cancer therapy
- Combines the direct cytotoxic effects of plasma with immune system activation
- Provides advantages over traditional inducers due to its multi-component nature
Plasma vs traditional inducers
- Plasma generates a complex mixture of reactive species (ROS, RNS) unlike single-agent inducers
- Produces both short-lived and long-lived reactive species for sustained effects
- Combines physical factors (electric fields, UV radiation) with chemical factors
- Allows for precise control of treatment parameters (dose, duration, composition)
- Demonstrates lower systemic toxicity compared to chemotherapy agents
Key molecular markers
- on the cell surface serves as an "eat me" signal
- ATP release acts as a chemoattractant for immune cells
- HMGB1 secretion promotes dendritic cell maturation and T cell activation
- Heat shock proteins (HSP70, HSP90) enhance antigen presentation
- Phosphatidylserine externalization indicates early-stage cell death
Damage-associated molecular patterns
- Endogenous molecules released or exposed during immunogenic cell death
- Include nucleic acids (DNA, RNA) that activate pattern recognition receptors
- Consist of proteins (HMGB1, S100 proteins) that stimulate immune responses
- Involve metabolites (ATP, uric acid) that act as danger signals
- Trigger the activation of innate immune cells (macrophages, dendritic cells)
Plasma components in cell death
- Plasma generates a complex mixture of reactive species and physical factors
- Different plasma components contribute to various aspects of immunogenic cell death
- Understanding the role of each component helps optimize plasma treatments
Reactive oxygen species
- Include hydroxyl radicals, superoxide anions, and hydrogen peroxide
- Induce oxidative stress leading to lipid peroxidation and protein oxidation
- Trigger mitochondrial dysfunction and release of pro-apoptotic factors
- Activate redox-sensitive transcription factors (NF-κB, Nrf2)
- Contribute to ER stress and unfolded protein response activation
Reactive nitrogen species
- Comprise nitric oxide, peroxynitrite, and nitrogen dioxide
- Cause nitrosative stress leading to protein nitration and S-nitrosylation
- Modulate cellular signaling pathways involved in cell death and survival
- Interact with ROS to form highly reactive species (peroxynitrite)
- Influence the immune response by modulating cytokine production
Electric fields and ions
- Generate transient pores in cell membranes (electroporation)
- Alter membrane potential and ion channel activity
- Induce calcium influx leading to ER stress and mitochondrial dysfunction
- Affect intracellular signaling pathways and gene expression
- Contribute to the synergistic effects of plasma treatment with other components
Cellular responses to plasma exposure
- Plasma treatment triggers a cascade of cellular responses leading to immunogenic cell death
- These responses involve multiple organelles and signaling pathways
- Understanding these mechanisms helps optimize plasma-based cancer therapies
Endoplasmic reticulum stress
- Induced by accumulation of misfolded proteins due to oxidative/nitrosative stress
- Activates the unfolded protein response (UPR) signaling pathways
- Involves three main UPR sensors (PERK, IRE1, ATF6)
- Leads to global protein synthesis inhibition and increased chaperone production
- Can result in apoptosis if ER stress is prolonged or severe
Calreticulin exposure
- Translocation of calreticulin from ER lumen to cell surface
- Serves as an "eat me" signal for phagocytes (macrophages, dendritic cells)
- Requires ER stress and activation of the PERK-eIF2α pathway
- Involves actin cytoskeleton remodeling for surface exposure
- Enhances immunogenicity of dying cells by promoting their uptake
ATP secretion
- Release of ATP through plasma membrane channels (pannexin-1)
- Acts as a "find me" signal for immune cells (monocytes, dendritic cells)
- Requires activation of caspases during early apoptosis
- Stimulates purinergic receptors (P2Y2, P2X7) on immune cells
- Promotes the recruitment and activation of antigen-presenting cells
HMGB1 release
- Passive from the nucleus during late-stage cell death
- Functions as an alarmin to activate innate immune responses
- Binds to pattern recognition receptors (TLR4, RAGE) on immune cells
- Promotes dendritic cell maturation and antigen presentation
- Enhances T cell activation and proliferation
Immunological consequences
- Plasma-induced immunogenic cell death triggers a cascade of immune responses
- These responses lead to the activation of both innate and adaptive immunity
- Understanding these processes helps develop more effective cancer immunotherapies
Dendritic cell activation
- Uptake of dying cancer cells and associated DAMPs by dendritic cells
- Maturation of dendritic cells characterized by upregulation of co-stimulatory molecules
- Enhanced antigen processing and presentation on MHC class I and II molecules
- Production of pro-inflammatory (IL-12, TNF-α) by activated dendritic cells
- Migration of mature dendritic cells to lymph nodes to prime T cells
T cell priming
- Presentation of tumor-associated antigens to naive T cells in lymph nodes
- Activation of CD4+ helper T cells and CD8+ cytotoxic T cells
- Expansion and differentiation of tumor-specific T cell clones
- Development of effector and memory T cell populations
- Generation of a diverse T cell receptor repertoire against tumor antigens
Adaptive immune response
- Infiltration of activated T cells into the tumor microenvironment
- Recognition and killing of tumor cells by cytotoxic T lymphocytes
- Production of anti-tumor cytokines (IFN-γ, TNF-α) by effector T cells
- Generation of tumor-specific antibodies by B cells
- Establishment of immunological memory for long-term tumor surveillance
Applications in cancer therapy
- Plasma-induced immunogenic cell death offers promising applications in cancer treatment
- Combines direct tumor cell killing with immune system activation
- Provides opportunities for synergistic combinations with existing therapies
Plasma-based immunotherapy
- Direct application of plasma to accessible tumors (skin, oral cavity)
- Use of plasma-activated liquids for systemic or localized treatment
- Combination of plasma treatment with immune checkpoint inhibitors
- Development of plasma-based cancer vaccines using treated tumor cells
- Potential for treating metastatic disease through abscopal effects
Combination with chemotherapy
- Synergistic effects of plasma treatment with traditional chemotherapy drugs
- Enhanced drug uptake due to plasma-induced membrane permeabilization
- Increased immunogenicity of chemotherapy-induced cell death
- Potential for dose reduction of chemotherapy agents to minimize side effects
- Overcoming drug resistance mechanisms through multi-modal treatment
Challenges and limitations
- Standardization of plasma devices and treatment protocols
- Optimization of plasma parameters for specific cancer types
- Penetration depth limitations for direct plasma application
- Potential for off-target effects on healthy tissues
- Need for large-scale clinical trials to establish efficacy and safety
Detection and measurement methods
- Accurate detection and measurement of immunogenic cell death markers essential for research
- Various techniques available to assess different aspects of the process
- Combination of multiple methods provides a comprehensive understanding
Flow cytometry techniques
- Quantification of surface-exposed calreticulin using fluorescent antibodies
- Measurement of phosphatidylserine externalization with Annexin V staining
- Detection of cell membrane permeability using propidium iodide or 7-AAD
- Analysis of mitochondrial membrane potential with JC-1 or TMRE dyes
- Assessment of intracellular ROS levels using DCFDA or DHE probes
Microscopy and imaging
- Visualization of calreticulin exposure using immunofluorescence microscopy
- Live-cell imaging to track ATP release with luciferase-based reporters
- Confocal microscopy to analyze subcellular localization of DAMPs
- Electron microscopy to examine ultrastructural changes during cell death
- In vivo imaging techniques to monitor tumor responses in animal models
Biochemical assays
- Quantification of extracellular ATP levels using bioluminescence assays
- Measurement of by ELISA or Western blot analysis
- Assessment of caspase activation using fluorogenic or colorimetric substrates
- Evaluation of DNA fragmentation through TUNEL assays or DNA laddering
- Analysis of oxidative stress markers (lipid peroxidation, protein carbonylation)
Clinical relevance and trials
- Plasma-induced immunogenic cell death shows promise for cancer treatment
- Clinical trials are ongoing to evaluate safety and efficacy in various cancer types
- Ethical considerations must be addressed for widespread clinical application
Current status of research
- Phase I/II clinical trials for plasma treatment of head and neck cancers
- Preclinical studies demonstrating efficacy in various solid tumor models
- Investigation of plasma-activated liquids for systemic cancer treatment
- Exploration of combination therapies with immunotherapy agents
- Development of standardized plasma devices for clinical use
Potential therapeutic outcomes
- Improved local tumor control through direct plasma application
- Enhanced systemic anti-tumor immunity against metastatic disease
- Reduced tumor recurrence rates due to immunological memory
- Potential for personalized treatment based on tumor immunogenicity
- Improved quality of life through minimally invasive treatment options
Ethical considerations
- Ensuring patient safety and minimizing side effects of plasma treatment
- Addressing potential long-term consequences of immune system activation
- Balancing the use of experimental therapies with standard of care
- Obtaining informed consent for novel plasma-based treatments
- Equitable access to plasma therapy across different patient populations
Future directions
- Plasma-induced immunogenic cell death research continues to evolve
- New approaches and technologies are being developed to enhance efficacy
- Integration with other cancer therapies offers promising opportunities
Personalized plasma treatments
- Tailoring plasma parameters based on individual tumor characteristics
- Development of biomarkers to predict response to plasma therapy
- Integration of genomic and proteomic data to optimize treatment protocols
- Customization of plasma-activated liquids for specific cancer types
- Adaptation of treatment schedules based on real-time monitoring of immune responses
Combination therapies
- Exploration of synergistic effects with immune checkpoint inhibitors
- Investigation of plasma treatment with CAR-T cell therapy
- Combination with oncolytic viruses to enhance immunogenicity
- Integration with targeted therapies to address multiple cancer pathways
- Development of multi-modal treatment protocols for advanced cancers
Technological advancements
- Design of plasma devices for minimally invasive or endoscopic applications
- Development of nanoparticle-based systems for targeted plasma delivery
- Improvement of plasma-activated liquid formulations for extended stability
- Integration of artificial intelligence for treatment planning and optimization
- Advancement of real-time monitoring systems for plasma-induced effects
Key Terms to Review (24)
Apoptosis: Apoptosis is a programmed cell death process that is crucial for maintaining cellular homeostasis and eliminating damaged or unwanted cells without causing inflammation. This mechanism is tightly regulated by various intracellular signaling pathways and can be influenced by external factors such as plasma treatment, which has been shown to induce apoptosis in certain cells.
Apoptotic Signaling Pathway: The apoptotic signaling pathway is a complex series of molecular events that lead to programmed cell death, known as apoptosis. This pathway is crucial for maintaining cellular homeostasis and regulating immune responses, especially in the context of immunogenic cell death where dying cells can trigger an immune response against tumors or pathogens. Understanding this pathway is essential for exploring how certain treatments, like plasma medicine, can induce cell death in a way that enhances the immune system's ability to recognize and attack cancer cells.
ATP secretion: ATP secretion refers to the process by which adenosine triphosphate (ATP), a crucial energy currency in cells, is released into the extracellular space. This release plays a significant role in various physiological processes, including cell signaling, immune response, and the induction of immunogenic cell death when influenced by plasma treatments. Understanding ATP secretion is essential for recognizing how cells communicate and coordinate their functions, particularly in the context of therapeutic applications.
Calreticulin exposure: Calreticulin exposure refers to the process where calreticulin, a chaperone protein found in the endoplasmic reticulum, is translocated to the cell surface during immunogenic cell death. This exposure acts as an 'eat me' signal for phagocytic cells, facilitating the recognition and uptake of dying cells by the immune system, which is crucial for eliciting an adaptive immune response.
Chemokines: Chemokines are a family of small cytokines that play a crucial role in immune responses by directing the movement of immune cells towards sites of inflammation, infection, or injury. They are involved in various physiological and pathological processes, including immunogenic cell death, where they help recruit immune cells to the dying tumor cells and promote a robust anti-tumor response.
Cold atmospheric plasma: Cold atmospheric plasma refers to a partially ionized gas at room temperature that contains a mix of charged particles, neutral atoms, and molecules. Unlike thermal plasmas, which can reach very high temperatures, cold atmospheric plasma operates at ambient conditions, making it suitable for various medical applications, particularly in disinfection, sterilization, and tissue regeneration.
Cytokines: Cytokines are small proteins that are crucial for cell signaling in the immune system, playing a key role in the communication between cells. They help regulate immunity, inflammation, and the formation of blood cells, acting as messengers that inform immune cells about infections or injuries. Their involvement in cellular pathways, wound healing, and cell death makes them vital for understanding various biological processes and therapeutic strategies.
Dendritic Cell Activation: Dendritic cell activation is the process by which dendritic cells, critical players in the immune system, undergo maturation and enhance their ability to present antigens and stimulate T-cell responses. This activation is essential for initiating adaptive immunity, allowing dendritic cells to effectively capture and process antigens, migrate to lymph nodes, and interact with naïve T-cells, thereby shaping the overall immune response.
Electric Fields and Ions: Electric fields are regions around charged particles where other charges experience a force. In the context of plasma medicine, these electric fields play a crucial role in influencing the movement of ions, which are charged atoms or molecules. The interaction between electric fields and ions is vital for understanding how plasma can induce immunogenic cell death, as this process relies on the effective targeting and alteration of cellular environments through ion activity.
Endoplasmic Reticulum Stress: Endoplasmic reticulum (ER) stress occurs when the ER, a cellular organelle responsible for protein folding and processing, experiences an overload of misfolded or unfolded proteins. This condition triggers a cellular response known as the unfolded protein response (UPR), which aims to restore normal function by enhancing protein folding capabilities, degrading misfolded proteins, and, if necessary, inducing apoptosis. In the context of immunogenic cell death, ER stress can influence how cells respond to stress and can affect their ability to elicit immune responses.
Flow Cytometry: Flow cytometry is a laser-based technology used to analyze the physical and chemical characteristics of cells or particles as they flow in a fluid stream. This method allows researchers to assess cellular responses to treatments, such as plasma therapy, by measuring various parameters like cell size, granularity, and the presence of specific surface markers.
Hmgb1 release: HMGB1 release refers to the process by which high mobility group box 1 (HMGB1) protein is secreted by cells, particularly during instances of cell stress or death. This protein acts as a key mediator in immunogenic cell death, signaling to the immune system and influencing various cellular responses. Its release plays a significant role in the immune response by promoting inflammation and the activation of immune cells, particularly in the context of therapeutic interventions like plasma medicine.
Immune checkpoint modulation: Immune checkpoint modulation refers to the process of enhancing or inhibiting the immune response by targeting specific proteins that regulate immune cell activation. This approach is crucial in immunotherapy, particularly in cancer treatment, as it can help reactivate immune responses against tumors by overcoming inhibitory signals that cancer cells exploit. By manipulating these checkpoints, immune checkpoint modulation aims to create a more effective anti-tumor immune response, which is particularly relevant when discussing the effects of various therapies such as plasma medicine on tumor cells.
Immunohistochemistry: Immunohistochemistry is a laboratory technique used to visualize the presence and location of specific proteins in tissue sections using antibodies. This method plays a crucial role in understanding the immune response, particularly in identifying markers associated with immunogenic cell death, which is a key aspect of therapeutic strategies in plasma medicine.
Necrosis: Necrosis is a form of cell death that occurs when cells are damaged in a way that leads to their unregulated breakdown, often resulting from factors like injury, infection, or insufficient blood supply. Unlike apoptosis, which is a programmed and controlled process, necrosis can trigger inflammation and affect surrounding tissues, making it significant in understanding various cellular responses to damage.
Plasma dermatology: Plasma dermatology refers to the use of cold atmospheric plasma in dermatological applications, primarily for treating skin conditions and promoting skin health. This innovative approach harnesses the unique properties of plasma to enhance wound healing, reduce inflammation, and stimulate tissue regeneration. Its significance is seen in the context of immunogenic cell death and emerging applications in plasma medicine.
Plasma oncology: Plasma oncology is a specialized field of research and application that focuses on using plasma technology to treat cancer through mechanisms like immunogenic cell death and other therapeutic strategies. It leverages the unique properties of cold plasma to interact with cancer cells, enhancing the immune response and potentially leading to innovative cancer treatments. This emerging approach represents a significant development in the broader landscape of plasma medicine, offering new avenues for tackling malignancies.
Reactive Nitrogen Species: Reactive nitrogen species (RNS) are highly reactive molecules that contain nitrogen and play essential roles in various biological processes, including signaling pathways and defense mechanisms. These species, such as nitric oxide (NO) and peroxynitrite (ONOO−), can modulate cellular functions, influence inflammation, and contribute to the antimicrobial properties of non-thermal plasma treatments in medical applications.
Reactive Oxygen Species: Reactive oxygen species (ROS) are highly reactive molecules that contain oxygen, such as free radicals and non-radical derivatives. They play a crucial role in cellular signaling, but excessive ROS can lead to cellular damage, influencing processes like apoptosis, inflammation, and various disease states.
Reactive Species Theory: Reactive Species Theory refers to the concept that reactive oxygen species (ROS) and reactive nitrogen species (RNS) generated during plasma exposure can significantly impact cellular functions and induce immunogenic cell death. This theory highlights how these reactive species can trigger cellular responses that lead to the activation of immune responses, making it essential in understanding how plasma treatments can be utilized for therapeutic purposes.
Release of HMGB1: The release of HMGB1 refers to the process by which High Mobility Group Box 1 (HMGB1), a nuclear protein, is expelled from cells into the extracellular space, often during cell death or stress responses. This event is crucial for immunogenic cell death, as HMGB1 acts as a danger-associated molecular pattern (DAMP) that signals to the immune system, promoting an inflammatory response and potentially leading to tumor rejection.
T Cell Response: The T cell response is a crucial part of the adaptive immune system where T cells recognize and respond to specific antigens presented by antigen-presenting cells. This response is essential for the body's defense against pathogens and cancer cells, involving the activation, proliferation, and differentiation of T cells into effector cells that can eliminate infected or abnormal cells. The T cell response also plays a key role in immunogenic cell death, particularly in the context of therapies involving plasma.
Thermal plasma: Thermal plasma is a state of matter where the gas is ionized, and the electrons and ions are at thermal equilibrium with each other, meaning they have similar temperatures. This type of plasma typically exists at high temperatures, allowing it to efficiently transfer energy to matter, which makes it crucial in various applications, especially in medical and industrial fields.
Tumor ablation: Tumor ablation is a medical procedure that involves the targeted destruction of tumor cells using various techniques to eliminate or reduce the size of the tumor. This process can effectively remove or shrink tumors, making it a crucial strategy in cancer treatment that leverages methods like heat, cold, chemicals, and even plasma-based technologies to achieve desired outcomes.