Immunoediting

Immunoediting is the process by which the immune system and tumor cells interact to create immune-resistant tumor growths. A tumor, also referred to as a neoplasm, is an uncontrolled growth of tissue in the body. Tumors can spread throughout the body and cause diseases such as cancer. Tumors can also remain at one site in the body and not cause harm. Immunoediting involves the body's innate, or immediate, immune system responses as well as adaptive, or specialized, immune system responses. It consists of three phases: elimination, equilibrium, and escape. During these phases, the body's immune system recognizes a tumor cell as a foreign agent and attempts to remove it from the system. Tumor cells that elude elimination are placed in a dormant state, in which they can undergo changes and create new immune system responses. If the immune system cannot keep the tumor cell in its dormant phase, the cell escapes and grows, which can lead to disease.

Background

Researchers have been studying the immune system's effect on tumor growth in organisms for many decades. Scientific arguments centered on the nature of the immune system's effect, specifically whether it was affecting tumor growth positively, negatively, or neutrally. Immunologists knew that the immune system was capable of detecting the invasion of pathogens, or viruses, in the body but knowledge of the immune system's effect on tumors remained untouched upon until the early twentieth century. In 1909, German scientist Paul Ehrlich proposed the immune system was able to monitor the host of an abnormal growth of tissue in the body. The idea was broached again fifty years later by immunologists Frank Macfarlane Burnet and Lewis Thomas. Burnet and Lewis believed the immune system was capable of recognizing cells experiencing new and abnormal changes in tissue growth and could work to eliminate the cells before the tumor growth spread, a concept they termed "immune surveillance" or "immunosurveillance."

The concept of immune surveillance was only one facet of the immune system's role in tumor growth, however. Future studies refined and elaborated on this concept, with many researchers theorizing the immune system was capable of more than just serving as the body's lookout for abnormal cells. Direct evidence of immune surveillance and its implications was not formally demonstrated in experiments until 2001, when immunologist Robert D. Schreiber and his colleagues compared the incidence of benign and malignant tumors in aging wild-type mice to mice without a recombination-activating gene 2 (RAG2). The RAG2 gene is responsible for variable (V), diversity (D), and joining (J) gene recombination, a process that generates B cells and T cells, which play a major role in the body's response to harmful foreign materials such as viruses, bacteria, and parasites. B cells and T cells generate antibodies—proteins that fight infections—to fight foreign materials and help the body build an adaptive immune system. The mice without the RAG2 gene could not generate these processes and therefore had no adaptive immune response.

Schreiber's experiment showed that mice without an adaptive immune response had a higher instance of cancerous growths and were also more susceptible to carcinogens, or cancer-causing agents. The wild-type mice, however, had far fewer tumor growths and were less susceptible to carcinogens. This showed that a portion of the tumor cells present in the RAG2-deficient mice were being identified and eliminated in the wild-type mice with an intact immune system. Tumors that did grow in the wild-type mice were found to be less immunogenic, or less able to produce an immune response, and grew in mice with and without an intact immune system. Schreiber used the term "immunoediting" to describe the process by which the body's immune system interacts with tumors.

Overview

When engaging in immunoediting, the body is not only protecting itself from cancerous growths but also shaping the makeup of developing tumors. To better organize this complex process for continued research, scientists divided immunoediting into three phases: elimination, equilibrium, and escape. Evidence showing the elimination phase of immunoediting primarily exists within scientific studies on mice, while the equilibrium and escape phases have been inferred from both mice and human trials.

The elimination phase of immunoediting can be described as immune surveillance. This phase utilizes both the innate and adaptive immune system to sense and destroy tumors before they grow into visible masses. With the innate immune system, the presence of tumor cells produces inflammatory signals. This initiates the activation of T cells and natural killer cells, which flood to the site of the tumor cells. These cells invade a tumor cell and produce secreted proteins called cytokines, which kill the tumor cells through one of several protein or oxygen-related tumor cell-killing mechanisms. While tumor cell death is in process, the body begins to produce chemokines, which block new blood vessel formation so the tumor cells cannot travel further. Immune system cells known as dendritic cells absorb what remains of the tumor cell following its destruction. The dendritic cells then travel to the lymph nodes for drainage. Tumor-saturated dendritic cells activate the development of T cells, which destroy any remaining immunogenic tumor cells.

The second step in immunoediting is the equilibrium phase. In the equilibrium phase, tumor cells that did not activate an innate immune response and escaped the elimination phase continue to grow until the adaptive immune system responds. The immune system holds the tumor in a dormant, yet functioning, state, allowing it to undergo changes. This is the editing phase of immunoediting, as it is when changes to immunogenicity occur. During this phase, tumor cells have the ability to evolve and elude immune system recognition, leading to immunosuppression, or the suppression of the body's healthy immune response. Cytokines also play a role in the equilibrium phase as the immune system attempts to balance the anti-tumor and tumor-supporting cytokines. If the tumor cells cannot be eliminated as a result of immunogenic edits, the equilibrium phase can last for years, and in some instances, for the entirety of the host's life.

If the immune system is no longer able to hold tumor cells in a state of dormancy, the body enters the escape phase of immunoediting. During this phase, tumor outgrowth is no longer controlled by the immune system and escapes into the body. Escape is made possible due to a number of factors, such as the immune system's inability to further produce anti-tumor T cells and natural killer cells. Immunosuppression can also lead to tumor-cell escape. Without immune system regulation, the tumor is able to grow and spread, which can lead to diseases such as cancer.

Bibliography

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