In next week’s post we are going to talk about immunotherapy, specifically adoptive cell transfer (ACT), the process of utilizing laboratory techniques to improve or expand the patient’s immune cells and return them to the body to fight the cancer. In histology, we see this in therapies like CAR-T cell therapy, which is on the cutting edge of cancer treatment. Before we dive into that though, let’s take a look at the basics behind the immune system.
There are different types of immune cells that make up the innate immune system and the adaptive immune system. The innate immune system includes neutrophils, eosinophils, basophils, mast cells, macrophages, dendritic cells, natural killer cells. The innate immune system is the body’s immediate and non-specific response to a threat. The adaptive immune system on the other hand, is the body’s second line of defense. This response takes time to develop but is specific to a unique pathogen. These cells include T-cells and B-cells (lymphocytes).
To break it down even further, there are different types of T-Cells (so named because they come from the thymus, vs B-Cells which come from the bone marrow). You might hear them referred to as CD4 T-cells and CD8 T-cells, or cytotoxic, helper, and regulatory T-cells.
CD8 is the co-receptor on cytotoxic T-cells, which helps the T-cell receptor (TCR) and the major histocompatibility complex type I molecules in identifying infected cells to kill them.
CD4 is the co-receptor on helper T-cells, which work with the TCR and major histocompatibility complex type II molecules, but this time it is recognizing a peptide on an antigen presenting cell. When a helper T-cell recognizes this peptide, they start to produce cytokines, which are proteins that help with cell signaling in the immune system.
Regulatory T-cells also have CD4 but their job is to shut down the immune response when it is no longer needed so the body doesn’t do damage to itself. They do this by producing inhibitory cytokines, killing cytotoxic T-cells, as well as releasing mediators that cause antigen presenting cells to down regulate their ability to present antigens. This is important because regulator T-cells can accidently get in the way of immune response to tumors, as can some macrophages that also down-regulate immune response.
A little background on the immune response to tumors. There are three phases, elimination, equilibrium, and escape. In the elimination phase, the immune cells like T-cells are trying to kill the tumor. They kill all of the tumor cells that they are able to kill, but there are still some malignant cells that are left behind that the immune cells can’t kill (equilibrium). These tumor cells that have adapted to avoid immunity will then grow (escape). So, despite the immune system’s best efforts, it can’t completely kill the tumor.
That’s where immunotherapy comes in. In our next post, we will be talking about the role that T-cells play in immunotherapy. Immunotherapy relies on the ability to add receptors to the T- cell to help it either recognize a new specific antigen, as in CAR-T cell therapy, or bind with the MHC on target antigens, as in T-cell receptor engineering.
Our next post also talks about emerging therapies using natural killer cells. As mentioned previously, natural killer cells, or NK cells, have typically been thought of as part of the innate immune system, but more recent research has identified characteristics that are similar to the adaptive immune system. Natural killer cells don’t require the MHC, in fact they target cells with low to no MHC class I molecules. Natural killer cells have an inhibitory receptor that generally stops them from killing regular healthy cells.
Tumor cells can sometimes adapt to reduce their MHC so they won’t be recognizable to the T-Cells. When they do this though, they become susceptible to natural killer cells. The inhibitory receptor is not triggered as there is not MHC so their activating receptor can engage with the tumor cell’s ligand and release granules to kill the tumor cell.
Unfortunately, reducing their MHC expression isn’t the only way tumors evade the immune system. They do everything in their power to create an immune tolerant environment around themselves, including making their own immune dampening cytokines. They can also consume the immune boosting cytokines that the immune cells are producing and activate T-cells to become T regulator cells to further inhibit immune response. Finally, tumor cells can induce immune checkpoint molecules like PD-L1.
These immune checkpoint molecules are proteins that bind to proteins on the T-cells to stop the T-cell from killing the cancer cell. Immune checkpoint inhibitors work as a cancer treatment by binding to the PD-L1 or other immune checkpoint molecule, to stop it from binding to the PD-1 on the T-cell so the T-cell can do it’s job of killing the cancer cell.
You can find more info about checkpoint inhibitors in the webinar, Checkpoint Inhibitors as Cancer Treatments, available on elearn.nsh.org.