The immune system protects the body by recognizing and eliminating foreign invaders like bacteria and viruses. This defense relies on identifying specific markers, known as antigens, which are typically fragments of proteins from these invaders. When cells become cancerous, they undergo changes that lead to the formation of new, abnormal proteins. These unique proteins can act as antigens, signaling to the immune system that something is wrong.
What Are Neoantigens
Neoantigens are a distinct class of proteins found exclusively on cancer cells and absent from healthy tissues. Unlike “self-antigens,” which are normal proteins ignored by the immune system, neoantigens are considered “non-self” or foreign. This difference makes them specific targets for immune responses against tumors. They are often unique to the individual patient, arising from specific genetic alterations within the cancer cells.
These novel proteins result from genetic changes within the tumor DNA, leading to altered amino acid sequences that form new peptide fragments. An immune response directed against them is less likely to harm healthy cells, offering an advantage for targeted cancer treatments.
How Neoantigens Form
Neoantigens primarily arise from somatic mutations within the DNA of cancer cells. These mutations are changes in the genetic code that occur after conception, meaning they are not inherited. Common types of somatic mutations that lead to neoantigen formation include point mutations, which are single nucleotide changes in the DNA sequence, and insertions or deletions (indels) of genetic material.
Once a gene is mutated, it is transcribed into messenger RNA (mRNA) and then translated into a protein with an altered amino acid sequence. The introduction of different amino acids changes the protein’s structure, which the immune system can then recognize as abnormal or non-self. While somatic mutations are the main drivers, neoantigens can also be produced through other mechanisms such as gene fusions, where two previously separate genes join together, or due to certain viral infections that alter cellular proteins.
Immune System Recognition
The immune system identifies neoantigens through specialized Major Histocompatibility Complex (MHC) molecules. These MHC molecules are located on the surface of cells, displaying small fragments of proteins, including neoantigens, to immune cells. There are two main classes: MHC class I and MHC class II.
MHC class I molecules present protein fragments from inside the cell, including those from mutated tumor proteins, to CD8+ T-cells, also known as cytotoxic T-lymphocytes. CD8+ T-cells are specialized immune cells that can directly kill abnormal cells. When a CD8+ T-cell’s receptor (TCR) recognizes a neoantigen presented by an MHC class I molecule on a cancer cell, it can trigger an anti-tumor immune response.
MHC class II molecules present protein fragments to CD4+ T-cells, or helper T-cells. These helper T-cells play a role in orchestrating the overall immune response, including supporting the function of CD8+ T-cells.
Neoantigens in Cancer Immunotherapy
The unique nature of neoantigens makes them valuable targets for modern cancer immunotherapy, offering a path toward more personalized treatments. One application is in the development of personalized cancer vaccines. These vaccines are designed by analyzing a patient’s tumor DNA to identify the specific neoantigens present. Synthetic versions of these neoantigens, often in the form of peptides or mRNA, are then used to create a vaccine tailored to that individual’s cancer. The goal is to train the patient’s immune system to recognize and attack their specific tumor cells while sparing healthy tissue.
Neoantigens also serve as biomarkers for predicting how a patient responds to immune checkpoint inhibitors. These inhibitors are a type of immunotherapy that works by “releasing the brakes” on the immune system, allowing T-cells to more effectively attack cancer cells. Tumors with a higher number of neoantigens, often referred to as a high tumor mutational burden, are more likely to respond well to checkpoint inhibitor therapy. Identifying these specific neoantigens helps in selecting patients who may benefit most from these treatments and in developing more precise and effective cancer therapies.