Tumour Immunology

I'm sure you have a vague idea of what cancer is- it's when cells keep on replicating even when you don't want them to. One thing that you might not know, however, is that the immune system can play a role in the growth (or lack of growth) of a tumour. And no, this has nothing to do with vague "boost your immune system!" claims found on many products in health stores.

Another thing that you most likely know about cancer is that it is caused by the accumulation of many mutations in several significant genes. These genes include RAS (a "proto-oncogene" responsible for cell signalling and differentiation), tumour-suppressive genes (e.g. P53) and genes regulating apoptosis (e.g. BAD). Factors that can make cancer development more likely include certain chemicals, pesticides, radiation, and some viruses such as HPV (leading to cervical cancer), Hepatitis B (leading to liver cancer) and Epstein-Barr Virus (which can lead to Burkitt's lymphoma, which is a tumour of B-lymphocytes). Even the Herpes virus can lead to a cancer called Kaposi's sarcoma, which manifests in abnormal purple skin lesions. This is especially likely to occur in HIV-positive patients.

Inflammation can also play a role in the development of cancer. Chronic inflammation increases cellular stress signals, which increases mutation rates in cells. Some pro-inflammatory cytokines can also induce cell proliferation. Another side-effect of inflammation is that it is pro-angiogenic, or promotes the growth of new blood vessels. These blood vessels can also help nourish the cancerous cells, or make it easier for tumour cells to invade into surrounding tissues.

Tumour Antigens

Tumour cells may express unique antigens, which help in recognition by lymphocytes. Antigens that are exclusively expressed by tumours are called tumour-specific antigens (TSAs), and include HPV E6. There are also tumour-associated antigens (TAAs), which are antigens that are either overexpressed, or expressed at the wrong time (i.e. a gene normally expressed during foetal development is expressed in an adult). An example of the former is HER2, which is overexpressed in breast cancer tumours.

The Immune Response to Cancer

Thankfully, we have a few ways in which we can fight back against cancer!

Innate responses

Many tumours express lower levels of MHC in order to try and "hide" from cytotoxic T-cells, but this comes back to bite them in the butt. As I've mentioned earlier, NK cells kill cells that have a reduced expression of MHC molecules. If there are mutations that cause NK cells to become less active, certain cancers may be more likely. Another innate response involves macrophages, which can secrete TNF-α. TNF stands for "tumour necrosis factor," and, true to its name, acts strongly against tumours.

Adaptive responses

Lymphocytes that can infiltrate tumours are known as tumour-infiltrating lymphocytes, or TILs. Most of these are T-cells. B-cells can also generate antibodies against TSAs.

Cytokines

There are several different cytokines that can also be helpful in cancer. Types I and II interferon (IFN) can both enhance anti-tumour activities, particularly type I IFN, which can induce tumour cell death. TNF-α can also exhibit anti-cancer effects, as I said above. IL-12 doesn't attack cancer cells directly, but it does help activate T_H1 and cytotoxic T-lymphocyte responses, which can help in the removal of a tumour.

All three systems work together, but they are not always perfect. In the best case scenario, there is an elimination phase in which the immune system can clear the cancerous cells before they become an issue (so basically the immune system wins). In the equilibrium phase, the immune system can get rid of some of the cells, but not all (so there's like a stalemate between the immune system and the cancer). In the escape phase, the cancer wins out, and cells that have managed to evade detection multiply and activate T-reg cells, suppressing further immune responses.

Immunosuppression by Tumours

The immune system might be able to fight against tumours, but the tumours can also fight back. They can do this by recruiting T-reg cells as well as myeloid-derived suppressor cells (MDSCs), the latter being related to macrophages (though have completely different functions). Soluble TGF-β and IL-10, which are anti-inflammatory cytokines, can also suppress the immune system.

As mentioned before, tumours may also express less MHC in order to evade detection.. The reduced amount of MHC may be due to mutations in genes for TAP and/or β₂-microglobulin. Tumour cells may also provide poor co-stimulatory signals to T-cells, leading to anergy and immune tolerance.

Cancer Immunotherapy

Understanding of the role of the immune system in cancer has led to some new therapies. In some of these therapies, monoclonal antibodies are given against TSAs or TAAs. An example of this is Herceptin, which acts against the HER2 receptor (a TAA) in breast cancer. Immunotherapies may also work to block DNA synthesis and cell division, or induce or enhance the immune response against tumours.

One such immunotherapy that achieves the latter is called adoptive cellular therapy. In this therapy, tumour-specific T-cells are obtained from the tumours or peripheral blood from patients and are mixed with cytokines in order to activate and expand these cells. Following this, cells are then re-infused.

There are also therapies that involve removal and re-infusion of dendritic cells. In these therapies, dendritic cells are either cultured with tumour antigens, causing them to express tumour peptides on MHC molecules, or they are transfected with plasmids expressing the tumour antigen, again for the purpose of their presentation on MHC molecules. These are re-infused into the patient, causing activation of tumour-specific T-cells.