The immune system identifies and eliminates threats by recognizing molecular markers called epitopes, which are protein fragments on the surface of cells. On a healthy cell, epitopes signal “self” to the immune system, preventing an attack. A neoepitope is a new or altered version of this marker that is not found in normal, healthy cells, marking the cell as an unrecognized entity.
The Origin of Neoepitopes
Neoepitopes are the direct result of genetic changes, called somatic mutations, that occur within tumor cells. These alterations to the DNA are not inherited but accumulate in cells over a person’s lifetime. When a mutation occurs in a protein-coding region of DNA, it can lead to the production of an altered protein not found in healthy cells.
Once these altered proteins are made, they are broken down inside the cell into smaller pieces called peptides. These peptides are then transported to the cell’s surface and displayed by specialized molecules known as the major histocompatibility complex (MHC). When a mutated peptide is presented on an MHC molecule, it forms a neoepitope.
Because these genetic mutations are specific to the cancer, the resulting neoepitopes are also exclusive to those cancer cells. They serve as highly specific markers, providing a clear distinction between cancerous and normal tissues. The number of mutations a tumor has, often referred to as the Tumor Mutational Burden (TMB), can correlate with the number of neoepitopes it presents. This variability means each person’s tumor has a unique set of neoepitopes.
Immune System Recognition
The immune system’s ability to combat disease relies on its capacity to distinguish between the body’s own healthy cells and abnormal cells. A specialized type of white blood cell, called a T-cell, is responsible for this surveillance process. T-cells are trained within the body to ignore “self” epitopes, preventing the immune system from attacking its own tissues and establishing a state of tolerance.
However, neoepitopes do not match the “self” profile that T-cells are trained to recognize. Because they arise from mutated proteins found only in tumor cells, they appear foreign to circulating T-cells. When a T-cell encounters a neoepitope presented on the surface of a cancer cell, it identifies the cell as abnormal. This recognition triggers the T-cell to activate and launch an attack intended to destroy the marked cell.
This interaction is the foundation of the body’s natural anti-tumor response. The immune system uses neoepitopes as signals to identify and eliminate cancerous cells. The presence of these unique markers allows for a targeted attack that spares healthy tissues.
Applications in Cancer Treatment
The discovery of neoepitopes has opened new avenues for developing highly targeted cancer therapies that leverage the body’s own immune system. Scientists can now identify the specific neoepitopes present on a patient’s tumor, paving the way for personalized treatments. These approaches are part of immunotherapy, a field focused on enhancing the immune system’s ability to fight disease.
One promising application is the development of personalized cancer vaccines. This process begins with sequencing the DNA from a patient’s tumor to identify the unique mutations it contains. From this genetic information, scientists can predict which neoepitopes are most likely to be recognized by the patient’s T-cells. A custom vaccine is then created containing these specific neoepitopes, which teaches the immune system to recognize and attack cancer cells bearing those markers.
Another technique is adoptive cell therapy. In this approach, T-cells that are already capable of recognizing a patient’s tumor neoepitopes are isolated from the patient. These specific T-cells are then multiplied in a laboratory before being reinfused. This infusion increases the number of cancer-fighting T-cells in the body, creating a highly targeted immune assault.
The quantity and quality of neoepitopes on a tumor can also help predict a patient’s response to certain existing immunotherapies. For example, tumors with a high number of neoepitopes often respond better to treatments known as checkpoint inhibitors, which work by releasing the natural brakes on T-cells. Analyzing a tumor’s neoepitopes helps clinicians determine which therapeutic strategies are most likely to succeed for an individual patient.