Adaptive Immunity & Cancer Neoantigens: a primer

Here I attempt to explain the basics of adaptive immunity and cancer neoantigens in a generally accessible way. Not being formally trained in immunology, I have striven to just cover the key concepts required for understanding the basic principals behind cancer neoantigens.

Adaptive Immunity

The adaptive immune system evolved as a method of detecting and destroying foreign pathogens, such as virus and bacteria. One of the key principles behind the adaptive immune system is that no prior knowledge of these foreign invaders is required; as a system it is prepared to handle any potential foreign entity.

One of the key players in the adaptive immune system is the T cell, named due to its maturation in the thymus. T cells have receptors on their cell surface called T cell receptors (TCRs) which are what recognize foreign proteins. All cells in the human body have identical copies of your DNA (well, aside from sperm and egg cells, but we will ignore those). All cells, except for T cells. During T cell development, the genes in the TCR locus get rearranged, or mixed up, creating diversity in this region. In addition to cutting and pasting genes around, nucleotides get randomly deleted and added, further increasing the diversity. All this mixing up results in a TCR which is essentially unique to that specific cell. Importantly, any T cell which would react to a self-protein (something non-foreign) is destroyed during development. This results in each person having a repertoire of over 1,000,000 different T cells each with different TCRs moving through their body, constantly looking for foreign proteins.

What is it that T cells actually recognize? In every cell of the body, genes in the DNA are expressed as proteins (chains of amino acids, typically hundreds to thousands of amino acids) inside the cell. Proteins do not last forever; there is an equilibrium that exists between proteins being created and degraded in the cell, so all proteins will eventually be broken down into short peptide fragments (shorter chains of amino acids, typically tens of amino acids). These peptides are transported into the endoplasmic reticulum where they are shortened some more, and may bind to waiting MHC molecules. MHC molecules have the job of presenting these short peptides (at this point 8-11 amino acids in length) to T cells. Once a peptide has bound to an MHC molecule, the peptide-MHC complex moves to the surface of the cell. Since, in the example shown below, the peptide is derived from a self-protein, T cells will survey the peptide-MHC complex, but none will recognize it as foreign, and the presenting cell gets left alone.

A quick note on MHC molecules: these are encoded by the most polymorphic regions of the genome (the HLA locus), resulting in thousands of different MHC molecules existing in Earth’s population. Each individual will have at most six of these different variants, and each variant can present only a subset of all peptides.

Returning to our cell example, if this cell is infected by a virus, this cell will now contain foreign proteins. Like self-proteins, these proteins will be broken down, transported into the endoplasmic reticulum, and may bind to an MHC molecule. When this foreign peptide-MHC complex is transported to the cell surface, one of the many T cells in the repertoire will recognize this peptide as foreign, and will initiate killing of the presenting cell.

After the T cell has killed the virally-infected cell, it will replicate itself, making more cells having that same TCR, allowing there to be a larger attack force of T cells able to hunt down other cells that have been infected by this same type of virus.

Cancer Neoantigens

Cancer is a disease of the genome. It is characterized by changes to cell’s DNA. Some of these changes are “silent” – they do not effect changes in proteins. However, many are “non-silent” – they cause a change in the protein sequence of self-proteins.

A subset of these mutations will be present in the broken down peptides that bind to the MHC molecules. These will be presented on the surface of the cell, and, due to the mutation, have the potential to be identified as foreign by T cells.

Importantly, these mutations are only present on cancer cells, so the immune response driven by the T cells will be specific for these cancer cells and should leave the rest of the normal cells alone.

This is the basis for many cancer immunotherapies, including:

  • Checkpoint blockade – helping existing T cells perform their attack
  • Cancer vaccines – vaccinating with the mutant peptides to “show” the T cells what to look for
  • Autologous T cell therapies – isolating T cells from a patient and selectively replicating the one(s) that recognize the cancer mutations before re-administering them into the same patient

Cancers can have many hundreds of mutations, so it becomes challenging to identify which subset of those mutations would make the best targets for these types of therapies. This is an active field of research, and one I am involved in.

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