New scientific work reveals that genetic heritage confers more or less protection against lung cancer induced by cigarette smoke. The cause: the existence of variations that modulate the effectiveness of the immune system.
Smoking is the main risk factor for lung cancer: it is estimated that between 80 and 90% of lung cancers are directly linked to it. However, not all smokers will necessarily be affected by this disease.
While some are spared by simple chance, others are spared for genetic reasons. Indeed, certain characteristics of their genetic heritage reduce their risk of developing the disease. A group of genes linked to the immune system is involved. Explanations.
How does the immune system work against cancer?
The immune system is best known for its role in defending against infections. However, 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 cancer that would threaten the body: recognized by the immune system, they are often eliminated before becoming problematic.
How does the immune system distinguish these cells from healthy cells in the body, which it does not attack? It is important to know that the accumulation of mutations that transform a healthy cell into a cancerous cell ends up modifying it. Its surface, in particular, carries molecules that distinguish it, in the eyes of agents of the immune system, 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. In doing so, they recover the antigens to present them to other immune cells, T lymphocytes, which further strengthen the antitumor response.
Antigens are not presented naked to T lymphocytes: they are bound to what are called major histocompatibility complex proteins. It is through these that the influence of genetic heritage on anti-cancer immunity is manifested, as recently demonstrated by a study published in the prestigious journal Science.
Genetic heritage influences immune response
In the course of this work, the researchers explored two biobanks, one in the United Kingdom and the other in Finland. These databases contain information on the habits, medical history and genetic heritage of hundreds of thousands of volunteers.
Their aim was to compare the profiles of participants who had lung cancer with those who had not developed it. In particular, they focused their attention on the sequences of genes coding for proteins of the major histocompatibility complex, which are therefore associated with the presentation of antigens to T lymphocytes.
Before diving into the heart of the matter, it may be useful to recall some notions of genetics. The information necessary for the production of the proteins that constitute us is carried by genes. Each gene is defined by a “sequence” that is specific to it (this term designates the chain of chemical “bricks” that constitute the gene).
Reading the sequence of a gene allows our cells to make the protein that corresponds to it, a bit like a plan is used to assemble a model.
It is considered that for a given gene, there is a “standard” sequence, which corresponds to that present in the majority of individuals. However, in some people, variations in the sequences are sometimes observed.
Proteins made from these slightly different genes may show variations from those made from the standard sequence. This partly explains the diversity we see in living things.
Furthermore, we all have our genes in duplicate, one received from our father and the other from our mother. Most individuals have the same sequence (most often standard) twice: they are said to be homozygous. The others are heterozygous, with a variation present on 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 in the gene group. HLA-II than those in the first group, who had had lung cancer.
They then demonstrated that this excess of heterozygous people was limited to participants who were smokers, active or former: 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 can these results be explained?
The presence of two different copies of genes HLA-II leads to a greater diversity of major histocompatibility complex proteins on the surface of antigen-presenting cells. This diversity is accompanied by an increased ability to present cancer antigens to T lymphocytes, and thus 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 tobacco is stimulated.
The first elements aimed at quantifying the effect of these variations suggest that an individual heterozygous in a specific location (we speak of locusplural loci) of a given gene of the complex HLA-II has a lung cancer risk reduced by about 30% compared to a homozygous person. It is conceivable that heterozygosity at multiple loci would be associated with a greater risk reduction.
It is important to remember, however, that regardless of genetics, the absence of exposure to tobacco remains the best way to protect against lung cancer!
An explanation for the success of immunotherapy
The links between genetic heritage and lung cancer have been known for several years. For example, we know that variations in genes that ensure DNA integrity can cause the disease in young non-smokers. The genes involved in smoker’s cancer therefore seem to be very different from those involved in cancer occurring in people who have never smoked.
However, this work is the first to convincingly demonstrate the link between genetic heritage, smoking, immune response and lung cancer.
This association between immunity and lung cancer explains the success of immunotherapies. These approaches, which consist of promoting the patient’s immune response by removing blocking mechanisms triggered by the body, have been integrated in recent years into the therapeutic arsenal used in thoracic cancerology, due to their sometimes spectacular effectiveness.
In the coming years, we can expect an explosion of knowledge in this field, which will certainly have implications for medical practice. Pulmonology and thoracic cancer teams are already seeking to develop lung cancer screening programs adapted to individual risk. There is little doubt that the progressive integration of genetic data will allow increasingly precise estimates.
Thanks to Professor Jacques Cadranel for his proofreading and comments.
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