The human body possesses intricate defense mechanisms designed to protect against threats, both external and internal. Among these sophisticated systems, the immune system plays a role in identifying and combating abnormal cells, particularly those associated with cancer. A significant component in this defense involves unique identifiers known as neoantigens. These specific markers allow the immune system to distinguish and target malignant cells.
Defining Neoantigens and Their Genesis
Neoantigens are novel proteins or parts of proteins that emerge from genetic alterations within cancer cells. They are not present in healthy, normal cells. They originate primarily from somatic mutations, which are changes in the DNA sequence that occur after conception and are not inherited. These mutations can include various types of DNA sequence modifications, such as point mutations where a single DNA base is altered, or insertions and deletions (indels) where DNA segments are added or removed.
When these DNA mutations occur within protein-coding regions of a gene, they can lead to an altered amino acid sequence in the resulting protein. These newly formed, altered proteins are then processed inside the cancer cells.
Following processing, small fragments of these altered proteins, the neoantigens, are presented on the cell surface. They are displayed by specialized molecules called Major Histocompatibility Complex (MHC) molecules. This presentation makes the cancer cell visible to the immune system. Unlike normal self-antigens, which are typically ignored by the immune system, neoantigens are perceived as foreign. This distinction is fundamental to their utility in cancer immunology.
Immune System’s Role in Neoantigen Recognition
The immune system’s ability to recognize neoantigens stems from their unique “non-self” characteristics. A specific type of immune cell, the T-cell, plays a central part in this recognition.
The recognition process begins when antigen-presenting cells (APCs) encounter and take up fragments of cancer cells, including their neoantigens. These APCs then process the neoantigens and display them on their own MHC molecules. The APCs subsequently present these neoantigen-MHC complexes to T-cells.
When a T-cell’s receptor (TCR) binds to a neoantigen presented on an MHC molecule, it triggers the T-cell to become activated. This activation leads to the proliferation of T-cells that recognize and eliminate cells displaying that particular neoantigen. This recognition is important for generating an effective anti-tumor immune response because neoantigens are largely unique to cancer cells, allowing the immune system to target malignant cells while generally sparing healthy tissues.
Therapeutic Applications in Cancer
The distinct nature of neoantigens makes them attractive targets for developing personalized cancer immunotherapies. Their presence solely on cancer cells means that therapies directed against them are less likely to harm healthy cells, reducing potential side effects.
One prominent application is the development of neoantigen vaccines. These vaccines train the patient’s immune system to recognize and attack the neoantigens found on their tumor.
Neoantigen vaccines involve identifying the specific mutations in an individual patient’s tumor through techniques like whole-exome sequencing. Based on this information, synthetic peptides, DNA, or RNA encoding these neoantigens are created to form a vaccine. When administered, the vaccine stimulates antigen-presenting cells to activate T-cells, boosting the immune response against cancer cells. Clinical trials have shown these vaccines can elicit robust T-cell responses and, in some cases, lead to tumor regression in various cancer types.
Another area of application is adoptive cell therapies (ACT), where immune cells are engineered to target neoantigens. This involves collecting T-cells from the patient, modifying them in the lab to recognize neoantigens, and then expanding their numbers before reinfusing them back into the patient. These engineered T-cells can then destroy cancer cells expressing the targeted neoantigens.
Identifying neoantigens also provides insights into predicting patient responses to other immunotherapies, such as immune checkpoint inhibitors. Tumors with a higher number of neoantigens, often referred to as a high mutational burden, tend to show a better response to these therapies. The presence of neoantigens can indicate that the immune system has more distinct targets, potentially leading to a more effective anti-tumor response when the immune system’s natural brakes are released by checkpoint inhibitors.