Unleashing the Potential of Cytokines: The Use of Immunotherapy Against Cancer
Discover how cytokines can play a key role in immunotherapy and the potential they hold in enhancing the immune response against cancer cells.
The interplay between the development of cancerous tumours and the immune response
In 1957, F.M.Burnet and L.Thomas formulated the theory of immunoediting, which consists of three phases: elimination, equilibrium and escape. During equilibrium, although potential cancer cells are being created every day, the immune system recognises and eliminates them at a faster rate than their production. However, when the rate of elimination increases to a certain point, the equilibrium stage is reached, where tumour cell proliferation equals the death caused by immunity. At this stage, the tumour is still sub-clinical. During the escape phase, the tumour variants have evaded the immune system and become clinically detectable. This theory demonstrates how cytotoxic innate and adaptive immune cells have the potential to control the development of cancerous tumours. However, cancer cells often evolve mechanisms which provide a level of protection against this immune response. Tumour cells can avoid attack from the immune system by avoiding recognition; and by creating an immunosuppressive TME (Tumour Microenvironment - a microenvironment which inhibits the immune response). Tumour cells avoid recognition by no longer expressing tumour antigens on the cell surface, so that cytotoxic T cells can no longer recognise and attack them. They can also down-regulate cell surface natural killer cell activators, so that natural killer cells are unable to recognise that the cancer cells are abnormal, and hence do not eliminate them. Tumour cells can instigate an immunosuppressive TME through immune checkpoint activation, which is when tumour cells express molecules which inhibit the immune response by interacting with immune cells’ checkpoints. They ca also create an immunosuppressive TME by the recruitment of cells such as regulatory T cells and myeloid-derived suppressor cells, which actively suppress the immune response; and the formation of new blood vessels, which create a hypoxic environment (one with low oxygen levels), and thus inhibit the functions of the immune cells by starving them from oxygen.
The role of cytokine-based immunotherapy
The progression through the three phases of immunoediting can be prevented through a type of immunotherapy which uses cytokines. 40% of non-small cell lung cancers have a genetic change in human leukocyte antigens, which means that they show fewer antigens, thus allowing them to hide from the immune system. Cytokines can be used to stimulate immune cells, such as T cells, B cells and natural killer cells, to identify and destroy foreign cells, including cancer cells. They can also cause inflammation at tumour sites, thus attracting more immune cells to that specific area. The first cytokine-based therapy was approved in 1986, for the treatment of hairy cell leukaemia. Since then, more therapies have been approved, including for the treatment of metastatic melanoma, follicular lymphoma and metastatic renal cell carcinoma. Cytokines are small glycoproteins and polypeptides which can influence the growth of cancer cells. Some can perpetuate, and some can inhibit the growth of tumour cells; thus specific cytokines can be administered in cancer treatment to enhance the immune response to cancer cells.
Adoptive cell therapy (ACT) is a type of immunotherapy, where immune cells are engineered or manipulated to increase their ability to recognise and destroy cancer cells. This could include isolating and genetically modifying T lymphocytes (a type of white blood cell), or isolating and activating / genetically modifying natural killer cells. These are then infused back into the patient’s body. Cytokines can be used throughout this process:
- To stimulate the growth of the culture of T cells / NK cells in the laboratory;
- To promote the cytotoxic functions of the T / NK cells;
- To prevent apoptosis (programmed cell death) in immune cells; or
- To aid in the migration of immune cells to the site of the tumour.
Cancer cells themselves can also be genetically modified to produce specific cytokines, which enhance nearby immune cells to attack the cancer cells. This limits systemic side effects, as the immune response can be localised to the area of the tumour.
Cytokines can also be used as adjuvants - substances added to vaccines to improve the potency of the immune response (such as activating T cells) to the vaccine’s target antigen. Different cytokines can be used to influence the specific type of immune response generated against the vaccine’s antigen - for example, some cytokines promote a humoral response (through the (production of antibodies), whilst others can promote a cell-mediated response (by stimulating cytotoxic T cells).
The AACR (American Association for Cancer Research) President-Elect Philip D. Greenberg, in his prediction for cancer research and treatment advances for 2023, mentioned cytokine technologies as a way forward into more immunogenic, and thus more potent cancer vaccines. In the realm of cancer immunotherapies, cytokine treatments fall under the category of active therapies - therapies which engage the patient’s own immune system. Whilst cytokine therapy is limited by a short half-life, the necessity for high doses, and systemic toxicity, there is great potential for future use, especially combined with other therapies, to enhance anti-tumour response.
Bibliography:
https://www.youtube.com/watch?v=He7xQn3-oL0
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4085883/
https://www.nature.com/articles/s43018-022-00418-6
https://www.onclive.com/view/a-new-generation-of-cytokine-based-immunotherapy-takes-shape