By Patrick Benusiglio - University Lecturer and Hospital Practitioner at AP-HP.Sorbonne University, specialist in genetic predispositions to cancer, Sorbonne University
New scientific research reveals that genetic makeup provides varying degrees of protection against lung cancer induced by cigarette smoke. The reason: the existence of variations that modulate the efficiency of the immune system.
Tobacco is the leading risk factor for lung cancer:
it's estimated that between 80 and 90% of lung cancers are directly linked to it. However, not all smokers will necessarily develop this disease.
Illustrative image Pixabay
Some people avoid it simply by chance, while others are spared due to genetic reasons. Indeed, certain genetic characteristics reduce their risk of developing the disease. A group of genes linked to the immune system is involved. Here's how.
How does the immune system fight cancer?
The immune system is mostly known for its role in defending against infections. However, its role in anti-cancer defense is just as crucial. In the lungs, as in other organs, cells that become cancerous
do not always develop into a full-blown cancer threatening the organism: when recognized by the immune system, they are often eliminated before becoming problematic.
How does the immune system distinguish these cells from the body's healthy cells, which it doesn't attack? It's important to understand that the accumulation of mutations that transforms a healthy cell into a cancerous one eventually alters it. In particular, its surface presents molecules that differentiate it, in the eyes of the immune system's 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 gather the antigens to present them to other immune cells, including T-lymphocytes, which further strengthen the anti-tumor response.
Antigens are not presented bare to T-lymphocytes; they are attached to what are called major histocompatibility complex (MHC) proteins. It is through these that the genetic makeup's influence on anti-cancer immunity is expressed, as recently demonstrated by a
study published in the prestigious journal Science.
Genetic makeup influences immune response
In this study, researchers explored two biobanks, one in the UK and the other in Finland. These databases contain information about the habits, medical history, and genetic makeup of hundreds of thousands of volunteers.
Their goal was to compare the profiles of participants who experienced lung cancer to those who hadn't developed it. They paid particular attention to the sequences of the genes encoding for MHC proteins, which are associated with the presentation of antigens to T-lymphocytes.
Before diving into details, it may be helpful to recall a few key genetic concepts. The information necessary for producing the proteins that make us who we are is carried by our genes. Each gene is defined by a "sequence" that is unique to it (this term denotes the specific arrangement of the chemical "building blocks" that make up the gene).
Reading the sequence of a gene allows our cells to produce the corresponding protein, much like a blueprint is used to assemble a model.
It is generally considered that for a given gene, there exists a "standard" sequence, which corresponds to the one present in most individuals. However, some people display variations in their sequences.
Proteins made from these genes, which slightly differ from the standard, can show variations compared to those derived from the standard sequence. This partly explains the diversity observed among living beings.
Additionally, we all carry two copies of each of our genes, one inherited from our father, the other from our mother. Most people have the same sequence twice (usually the standard one): they are said to be homozygous. Others are heterozygous, meaning they possess a variation on one of the two copies.
When studying the British and Finnish biobanks, researchers noticed that participants from the second group, who had not developed lung cancer, were more frequently heterozygous for certain sequences of the
HLA-II gene group compared to those from the first group, who had experienced lung cancer.
They further demonstrated that this excess of heterozygous individuals was limited to smoking participants, either active or former smokers: it was not observed in people who had never smoked. This finding indicates that the protective effect of genetic variations is specific to smokers.
How can these results be explained?
The presence of two different copies of
HLA-II genes leads to a greater diversity of MHC proteins on the surface of the antigen-presenting cells. This diversity is associated with an increased ability to present cancerous antigens to T-lymphocytes, and thus a better immune response.
To explain why the protective effect is only observed in smokers, it is hypothesized that only immunity against tobacco-induced cancer types is stimulated.
Preliminary estimates aiming to quantify the effect of these variations suggest that a heterozygous individual at a particular location (locus, plural loci) of a given
HLA-II gene has about a 30% reduced risk of lung cancer compared to a homozygous person. It can be imagined that heterozygosity at multiple loci would be associated with an even greater risk reduction.
However, it is important to remember that, regardless of genetics, avoiding tobacco exposure remains the best way to protect oneself against lung cancer!
An explanation for the success of immunotherapy
The links between genetic makeup and lung cancer have been known for several years. For instance, it is known that variations in genes ensuring DNA integrity
can cause disease in young non-smokers. The genes involved in smoker-related cancer thus appear to be quite different from those involved in cancer occurring in individuals who have never smoked.
However, this research is the first to convincingly demonstrate the link between genetic makeup, smoking, immune response, and lung cancer.
This association between immunity and lung cancer explains the success of immunotherapies. These approaches, which
aim to enhance the patient's immune response by removing blocking mechanisms triggered by the body, have been integrated into
the arsenal used in thoracic oncology in recent years, due to their sometimes spectacular effectiveness.
In the coming years, an explosion of knowledge in this field can be expected, which will undoubtedly have implications for medical practice. Pulmonology and thoracic oncology teams are already working on developing lung cancer screening programs tailored to individual risk. There is little doubt that the gradual integration of genetic data will lead to increasingly precise risk estimates.
Thanks to Professor Jacques Cadranel for his review and comments.