The immune system in the fight against cancer

Professor Greta Guarda, Full Professor at the Faculty of Biomedical Sciences at Università della Svizzera italiana (USI), and Professor Roger Geiger, Associate Professor at USI Faculty of Biomedical Sciences, reviewed the progress of immunotherapy in oncology in an article written in collaboration with laRegione.

William Coley was an American surgeon who lived during the latter half of the 19th century and the early 20th century. He observed that some tumours would shrink following acute infections. This led him to suggest that a strong activation of the inflammatory and immune responses could help inhibit tumour growth. As a result, Coley began treating patients with a bacterial preparation. Although the documentation and standardisation of procedures are insufficient for a rigorous evaluation of the effectiveness of the therapies, they represent the first attempt to activate the immune system against tumours. Over the last century, our understanding of the immune system has advanced significantly. We now know how a specific type of cell, called cytotoxic T lymphocytes, recognises and eliminates cells in our body that contain "inappropriate" material, such as those infected by a virus. Additionally, in the 1990s, researchers discovered mechanisms that "brake" T cells in the immune system, preventing overly strong reactions that could harm healthy cells.

However, tumours also exploit these "mechanisms" to circumvent the defence provided by cytotoxic T cells. In fact, cytotoxic T lymphocytes can recognise the mutated – and therefore "inappropriate" – material typically found in cancer cells and eliminate them. Unfortunately, cancer cells can also use these same "molecular brakes" to avoid being destroyed.

These discoveries were awarded the Nobel Prize in Physiology and Medicine in 2018 to researchers James Allison of the United States and Tasuku Honjo of Japan.

How do lymphocytes recognise cancer cells?
T cell receptors (TCRs) and antigen-presenting molecules play a crucial role. These molecules are produced by our cells to present fragments of proteins, known as antigens, to cytotoxic T lymphocytes. When the cytotoxic T lymphocyte receptor recognises that the cell's contents are "improper", the lymphocyte is activated and destroys the infected or cancerous cells. In the case of cancer cells, the recognition process depends not only on the interference of the "molecular brakes" mentioned above, but also on the antigen presentation capacity, which is often altered in tumour cells. For years, Greta Guarda's group at the Institute for Research in Biomedicine in Bellinzona has been studying the mechanisms that regulate antigen presentation to exploit the potential of T lymphocytes fully. In this context, it has contributed to characterising a new mechanism that is often suppressed in tumour cells to escape cytotoxic T lymphocytes.

Immunotherapies in our reality
The advancements in molecular biology and biotechnology have led to the creation of a new array of therapies, particularly monoclonal antibodies, that can "disarm" the mechanisms that inhibit immune responses. This allows T lymphocytes to be activated against cancer cells. In 2011, the United States approved the first antibody designed to block the CTLA-4 "brake" for the treatment of advanced metastatic melanoma. This marked a groundbreaking moment, demonstrating for the first time that a drug harnessing the immune system can significantly extend the survival of specific patients. Subsequently, antibodies against a second "brake mechanism" known as "PD-1" were approved. Initially used for melanoma, these antibodies are now also used for lung cancer, kidney cancer and other tumours. Examining our own situation at the Oncology Institute of Southern Switzerland (IOSI) of Ente Ospedaliero Cantonale, these approaches have been employed for several years and in various types of cancer. In particular, they have significantly improved the prognosis for patients with melanoma and lung cancer. The IOSI has conducted studies on developing immune therapies, and several clinical trials for new immunotherapies are currently ongoing, providing significant opportunities for patients.

The limitations of immunotherapy and the importance of research

While these antibodies have significantly improved the prognosis for many patients, there is still room for advancement in several areas. Currently, only a portion of patients—estimated to be between 20% and 30%—respond to these therapies effectively over the long term. This limitation is why researchers are actively exploring other methods to reactivate cytotoxic T cells. For instance, a research team led by Roger Geiger at the Institute for Research in Biomedicine in Bellinzona is investigating how tumours suppress immune cells. They are employing genetic screening to identify new "molecular brakes" that tumours use to inhibit the activity of cytotoxic T cells. In the future, these mediators could potentially be blocked by specific antibodies, providing an additional strategy to enhance the effectiveness of immunotherapies. But other aspects need to be improved. In some patients, the immune system responds to immunotherapy by also attacking healthy cells. This reaction can lead to various side effects, ranging from mild dermatitis to severe complications that require careful medical management. Additionally, monoclonal antibodies are more expensive to produce than other types of medications, which not only raises healthcare costs but also limits access to these treatments in less affluent countries. Therefore, it is essential to continue researching the mechanisms that regulate the immune response to tumours. Greta Guarda's research group is investigating how the "braking" effects of PD-1 influence cytotoxic T cells. While PD-1 is a well-established clinical target known for its impact on cytotoxic T cells, the molecular mechanisms behind these effects remain a topic of debate. Understanding how these mechanisms operate could advance scientific research and provide insights into why some patients respond excessively or insufficiently to immunotherapies that target this "molecular brake."

In conclusion

Since the work of Coley, immunotherapy in oncology has undergone remarkable advancements, significantly improving the survival rates and quality of life for many patients. However, challenges still exist for those who do not respond to treatment, as well as issues related to side effects and high costs. Understanding the mechanisms that regulate antigen presentation and expanding our knowledge of "molecular brakes" could help explain the varying responses to treatment among patients. Additionally, this knowledge may provide new and complementary strategies for fighting cancer.

Content edited by the Institute for Research in Biomedicine (IRB) Bellinzona, affiliated with USI, on its 25th anniversary, in collaboration with laRegione.