Immunogenic cell death (ICD) is a specific type of cell demise that activates an immune response in the body. Unlike other forms of cell death, ICD uniquely signals the immune system to recognize and target dying cells. This distinct characteristic makes it a subject of significant interest in fields such as cancer research, where it holds promise for novel therapeutic strategies.
Distinguishing Immunogenic Cell Death
Cell death is a fundamental biological process, broadly classified as regulated or accidental. Apoptosis, or programmed cell death, is a controlled process where cells die orderly, forming apoptotic bodies cleared by neighboring cells or macrophages. This process is considered “silent” or tolerogenic to the immune system, as it does not provoke an immune response.
Necrosis, in contrast, is an uncontrolled cell death triggered by external factors like injury, toxins, or infection. It involves rapid loss of cell membrane integrity, releasing cellular contents into the environment. While necrosis can induce inflammation, it does not lead to a specific anti-tumor immune response like ICD. ICD actively signals the immune system through specific molecular cues, leading to productive immune activation.
Molecular Hallmarks of Immunogenic Cell Death
ICD’s ability to trigger an immune response stems from the release or exposure of specific “danger signals” by dying cells. These molecules, known as Damage-Associated Molecular Patterns (DAMPs), are normally contained within healthy cells but become externalized or secreted upon cellular stress or death. DAMPs act as alarm signals, alerting and activating immune cells, particularly dendritic cells.
One significant DAMP is calreticulin (CRT), a protein that resides inside the cell’s endoplasmic reticulum. During ICD, calreticulin translocates to the cell surface, acting as an “eat-me” signal that promotes the engulfment of dying cells by phagocytes, such as dendritic cells. Its surface exposure is a prerequisite for the immunogenicity of dying cancer cells, though its presence alone is not sufficient to classify cell death as immunogenic.
Adenosine triphosphate (ATP) is another DAMP released into the extracellular space during ICD. Extracellular ATP acts as a “find-me” signal, attracting immune cells like dendritic cells and activating them through specific purinergic receptors, such as P2RX7. This activation can lead to the secretion of pro-inflammatory cytokines, like interleukin 1 beta (IL-1β), contributing to the immune response.
High Mobility Group Box 1 (HMGB1) is also a DAMP released during ICD. Normally found in the nucleus, HMGB1 is released from dying or stressed cells and signals tissue injury when present extracellularly. It activates Toll-like receptor 4 (TLR4) on dendritic cells, stimulating their maturation and the production of pro-inflammatory factors, thereby contributing to the immunogenicity of the dying cell.
Therapeutic Applications of Immunogenic Cell Death
Understanding and inducing immunogenic cell death has significant implications for therapeutic strategies, particularly in cancer treatment. Tumors are often characterized as “cold” or “hot” based on their immune cell infiltration. “Cold” tumors have low immune cell infiltration and are less responsive to immunotherapy, while “hot” tumors are rich in immune activity and more susceptible to immune-based treatments. Triggering ICD in cancer cells can transform a “cold” tumor into a “hot” one by eliciting innate and adaptive immune responses.
Certain conventional cancer therapies induce ICD, enhancing their anti-tumor effects. For instance, some chemotherapies, such as anthracyclines (like doxorubicin and mitoxantrone), oxaliplatin, and cyclophosphamide, can induce ICD. Radiation therapy and photodynamic therapy also induce ICD. These treatments not only eliminate cancer cells but also promote the release of DAMPs and tumor antigens, effectively turning dying cancer cells into an in-situ vaccine that stimulates long-lasting immunity against the tumor.
The knowledge that certain therapies can induce ICD informs new strategies in immunotherapy. Combining ICD-inducing agents with immune checkpoint inhibitors, for example, is a promising approach to enhance anti-tumor immunity. By activating the immune system through ICD and simultaneously removing the “brakes” on immune cells with checkpoint inhibitors, researchers aim to create a synergistic effect for effective and durable anti-cancer responses. This dual approach helps overcome the immunosuppressive environment often found within tumors, improving patient outcomes.