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By Melissa Bedard, MRC Human Immunology Unit, MRC Weatherall Institute of Molecular Medicine
October is a special time of year. The autumn leaves and crisp air mark the beginning of a new academic term. It also marks the annual announcements of the year’s Nobel Laureates, starting with the recipients of the Nobel Prize in Medicine and Physiology.
As scientists, we dream that our work today might revolutionise tomorrow – the kind of achievements that are recognised by a Nobel Prize. My research, like that of many immunologists, is primarily basic in nature. This year’s Nobel Prize in Medicine and Physiology is an exciting reminder that basic immunology discoveries can serve not only as key building blocks to better understanding fundamental immune cell function, but also as therapeutic targets in the fight against immune-mediated diseases.
From the lab bench to the clinic
This year’s recipients are Tasuku Honjo and James Allison for their discovery of PD-1 and CTLA-4 respectively. These two important molecules are expressed on the surface of T cells. Stemming from a branch of immune cells called lymphocytes, T cells have the ability recognise and kill unhealthy cells, such as virally infected cells, with a high degree of specificity. With a better understanding of how certain molecules, such as PD-1 and CTLA-4, control T cell function, scientists have discovered ways of manipulating T cell responses.
These findings laid the foundations for cancer immunotherapy, a revolutionary approach to treat cancer by enabling your own T cells to recognise and kill tumour cells. This strategy has dramatically changed cancer treatment, and has already benefited millions of individuals living with cancer. For example, before the implementation of cancer immunotherapy around 2010, the three-year survival rate for metastatic melanoma patients was just 10%. As of 2017, it was above 50%. Former American president Jimmy Carter received cancer immunotherapy for advanced melanoma that metastasised to the brain and is today cancer-free – just one example illustrating the power of cancer immunotherapy. Not only are patients’ lives extended, but they also have a better quality of life during treatment than with alternative therapies.
Tracing the immunology of cancer
To fully understand why cancer immunotherapy can be so effective, we must go back to fundamental immunology concepts. Immune cells can discriminate between the body’s own cells, termed ‘self’, and foreign pathogens, such as viruses and bacteria, termed ‘non-self’. Based on this discrimination,one’s immune cells will eradicate foreign pathogens while leaving the body’s own cells unharmed. However, the immune cells’ recognition of and response to tumours is a dynamic and complex matter. This is where the Nobel Prize-winning discoveries fit in.
There are several questions to consider when evaluating the immune response to cancer. Firstly, do immune cells infiltrate tumours? Immune cells extensively infiltrate so-called ‘hot’ tumours, whereas ‘cold’ tumours have few to no immune cells within the tumour tissue. Understanding why certain tumours are ‘hot’ while others are ‘cold’ is an intensive area of research, since immunotherapy, including that stemming from Honjo and Allison’s findings, would be most effective for treating ‘hot’ tumours.
Secondly, if present, are immune cells able to kill the tumour tissue? Even in ‘hot’ tumours, immune cells can be dysfunctional and therefore ineffective – an observation termed the ‘Hellstrom paradox’. Since immune cells are heavily influenced by their surroundings, the environment around the tumour might contribute to impaired anti-tumour immune responses. Certain signalling molecules, called cytokines, can shift the type of response mounted by immune cells. These cytokines act as messengers between cells and can be released from multiple cell types (immune and non-immune), including cancer cells themselves. One class of cytokines called interferons often promote tumour killing, while another cytokine, TGF-b, suppresses tumour killing. The relative abundance of such cytokines in the tumour surroundings can tip the balance between a pro- or anti-tumour immune response.
Binding of specific receptors to PD-1 and CTLA-4 on the surface of T cells (the molecules discovered by the newest Nobel Laureates) inhibits T cell function. Under normal circumstances, PD-1 and CTLA-4 help turn off T cell responses to prevent over-zealous and damaging inflammatory responses (which can contribute to autoimmune diseases like certain types of diabetes). However, in cancer, where T cells must retain prolonged killing abilities, the use of antibodies to block the PD-1 or CTLA-4 interaction with their specific receptors on tumour cells boosts T cell activity so that they remain ‘tumouricidal’. This clinical approach is termed ‘checkpoint therapy,’ the most successful form of cancer immunotherapy to date.
Finally, if infiltrating T cells are effective, can they recognise specific markers on the tumour to kill it? Tumours arise for many reasons, but mutations in the genetic code of individual cells – mutations that cause the cell to multiply unchecked, often contribute to tumour formation. However, these mutations can lead to the production of mutated ‘self’ proteins that no longer resemble normal proteins, and as such immune cells recognise them as ‘non-self’. These mutated proteins are termed ‘neoantigens’ and can be recognised by specific T cells that kill the neoantigen-expressing tumour cells. Identifying and harnessing the power of neoantigen-specific anti-tumour responses is at the forefront of cancer immunotherapy research, especially after Steve Rosenberg’s research group used a cocktail therapy including neoantigen-specific T cells and checkpoint therapy to cure a woman with late stage metastatic breast cancer.
Immunologists throughout Oxford, including those at the MRC Human Immunology Unit (MRC HIU) at the MRC Weatherall Institute of Molecular Medicine (MRC WIMM), are playing their part in advancing cancer immunotherapy research, particularly in addressing the three questions previously mentioned. Student-led research has centred on a molecule expressed by tumours that binds a receptor on T cells, similar to PD-1, which prevents T cells from infiltrating tumours. This interaction impairs T cells’ physical mobility by altering the cells’ actin cytoskeletons; collaborations between multiple labs in Oxford guided this research component. Other research also ongoing here in Oxford focuses on: (a) the affect of engineered antibodies against another inhibitory molecule, BTLA; (b) analysing tumour-specific T cell populations in melanoma patients over the course of their checkpoint therapy; and (c) fine-tuning the production of PD-1 on T cells to elicit effective anti-tumour responses while limiting a damaging inflammatory response.
Work at the MRC HIU also assesses how the tumour microenvironment contributes to anti-tumour immune responses. We investigate how immune cells are affected by stressful conditions, such as a lack of amino acids or oxygen. Based on these studies, we are assessing the therapeutic potential of manipulating metabolic enzymes differentially expressed in tumours versus immune cells.
Finally, there is ongoing and promising work on neoantigen discovery through understanding the mechanisms of neoantigen expression in ovarian cancer, melanoma, and glioblastoma multiforme, a type of brain cancer.
All of this exciting immunology research, from basic mechanisms of immune cell function to translation studies, will contribute to a growing pool of knowledge that can guide therapeutic interventions for cancer. This year’s Nobel Prize in Medicine illustrates that basic discoveries in fundamental immunology paired with creative and aspirational thinking can have far-reaching implications for the future of medicine. Scientists at the MRC WIMM, including myself, had the pleasure of hearing Dr Honjo speak about his work last year. As compelling as his research was (and is), it was equally inspiring to see that Nobel Prize winners are fellow, hard-working scientists with the curiosity and appetite to see how far their ideas will go.