How does the immune system fight cancer?
The immune system is best known for its role in defending against infection. Yet its anti-cancer role is just as important. In the lung, as in other organs, cells that become cancerous do not systematically end up giving rise to a cancer that would threaten the body: recognized by the immune system, they are often eliminated before they become problematic.
How does the immune system distinguish these cells from the body's healthy cells, which it does not attack? The accumulation of mutations that transforms a healthy cell into a cancerous one eventually modifies it. In particular, its surface carries molecules that distinguish it, in the eyes of immune system agents, from healthy cells. These molecules, recognized as foreign, are called antigens.
When antigens are detected on the surface of a cell, specialized immune cells take charge of destroying it. As they do so, they retrieve the antigens and present them to other immune cells, the T lymphocytes, which further strengthen the anti-tumor response.
Antigens are not presented naked to T lymphocytes: they are bound to what are known as major histocompatibility complex proteins. It is through these proteins that the influence of genetic inheritance on anti-cancer immunity is manifested, as recently demonstrated by a study published in the prestigious journal Science
Genetic inheritance influences the immune response
In the course of this work, the researchers explored two biobanks, one in the UK and the other in Finland. These databases contain information on the habits, medical history and genetic make-up of hundreds of thousands of volunteers.
Their aim was to compare the profiles of participants who had developed lung cancer with those who had not. In particular, they focused on the gene sequences coding for major histocompatibility complex proteins, which are associated with antigen presentation to T lymphocytes.
Before delving into the nitty-gritty of the subject, perhaps it's worth recalling a few notions of genetics. The information needed to produce the proteins that make us up is carried by genes. Each gene is defined by its own "sequence" (this term designates the sequence of chemical "building blocks" that make up the gene).
Reading the sequence of a gene enables our cells to make the corresponding protein, in much the same way as a blueprint is used to assemble a model.
For a given gene, a "standard" sequence is considered to exist, corresponding to the one present in the majority of individuals. However, in some individuals, sequence variations are sometimes observed.
Proteins made from these slightly different genes can have variations from those made from the standard sequence. This partly explains the diversity we observe in living beings.
What's more, we all have our genes in duplicate, one received from our father and the other from our mother. Most individuals have the same sequence twice (usually standard): they are said to be homozygous. Others are heterozygous, with a variation in one of the two copies.
By studying the British and Finnish biobanks, the researchers observed that participants in the second group, who had not had lung cancer, were more often heterozygous for certain sequences of the HLA-II gene cluster than those in the first group, who had had lung cancer.
They then demonstrated that this excess of heterozygous individuals was limited to participants who were active or former smokers: it was not observed in people who had never smoked. This observation indicates that the protective effect of genetic variations was therefore specific to smokers.
How do you explain these results?
The presence of two different copies of the HLA-II genes leads to a greater diversity of major histocompatibility complex proteins on the surface of antigen-presenting cells. This diversity is accompanied by an increased capacity to present cancer antigens to T lymphocytes, and hence a better immune response.
To explain why the protective effect is only observed in smokers, it is assumed that only immunity against the types of cancer caused by smoking is stimulated.
Initial evidence to quantify the effect of these variations suggests that an individual heterozygous at a specific locus (loci) of a given gene in the HLA-II complex has a 30% lower risk of lung cancer than a homozygous individual. It is conceivable that heterozygosity at several loci would be associated with a greater risk reduction.
Nevertheless, it's important to remember that, regardless of genetics, avoiding exposure to tobacco remains the best way to protect against lung cancer!
An explanation for the success of immunotherapy
The links between genetic inheritance and lung cancer have been known for many years. We know, for example, that variations in genes that ensure DNA integrity can cause the disease in young non-smokers. The genes involved in smoker's cancer therefore appear to be quite different from those involved in cancer in people who have never smoked.
However, this work is the first to convincingly demonstrate the link between genetic inheritance, smoking, immune response and lung cancer.
This association between immunity and lung cancer explains the success of immunotherapies. In recent years, these approaches have become part of the therapeutic arsenal used in thoracic oncology, thanks to their sometimes spectacular efficacy.
In the years to come, we can expect an explosion of knowledge in this field, which will certainly have implications for medical practice. Respiratory and thoracic oncology teams are already working to develop lung cancer screening programs tailored to individual risk. There is little doubt that the gradual integration of genetic data will enable increasingly precise estimates to be made.
Thanks to Professor Jacques Cadranel for his proofreading and comments.
Patrick Benusiglio, associate professor and Hospital Practitioner at AP-HP (the Paris Public Hospital System) and specialist in genetic predisposition to cancer, at Sorbonne University
This article is republished from The Conversation under Creative Commons license. Read the original article in French.
