The IrsiCaixa AIDS Research Institute conducted the study of a case of triple negative breast cancer This shows how cancer cells present themselves several genetic changesbut also protein and cellular processes that allow them to evade the body’s own defenses and immunotherapies.
The results are published in the journal Nature communication show that although the Immune reaction Although the fight against cancer remains stable until the end of the disease, the genetic complexity of cancer cells and their ability to evade immunity prevent victory.
“The patient’s follow-up was unique both in terms of follow-up time and the number of samples and parameters examined. “We examined every corner of the tumor and the person’s immune system for more than five years,” he explains. Leticia De Mattos ArrudaOncologist at IrsiCaixa during the study, senior lead author of the article and currently at BioNTech.
The patient’s follow-up was unique both in terms of follow-up time and the number of samples and parameters examined.
Triple negative breast cancer It is one of the most aggressive and difficult to treat as it does not respond to traditional treatments. However, immunotherapy is usually an option for these patients because they have many more mutations than the rest and make them visible to the immune system.
“We wanted to understand how the immune system manages to fight cancer at every stage of the disease and what mechanisms ensure that the immune system can no longer defeat it later,” notes De Mattos-Arruda.
In the picture the researchers De Mattos and De la Iglesia. / IrsiCaixa
Mutation and evasion of the immune system
The study has 112 samples from 12 patients of metastatic triple-negative breast cancer, including primary tumors and metastases present during the course of the disease and at the time of autopsy. In one of these patients, follow-up from diagnosis through metastatic progression to death was possible.
“We examined consecutive samples of blood, primary tumor and metastases using multi-omics techniques, which allow access to all information about the genes, proteins and even the cellular composition of the samples,” he explains. Núria of the church, co-author and researcher at IrsiCaixa. “The hardest part was getting these huge amounts of data and making sense of it.”
By filtering this data, it was found that the genetic and immunological variability is very high both within each tumor and between the different metastases and that some of these genetic changes give cancer cells the opportunity to evade the body’s defenses.
The mechanisms by which cells avoid them are very diverse, ranging from preventing the production of inflammatory molecules that attract immune cells to the tumor to hiding tumor proteins that are recognized by the immune system.
More importantly, the study shows that these mechanisms all act simultaneously and synergistically within the same tumor, leading to disease progression despite the immune system’s continued efforts to fight them.
Combined therapies to combat it
The team has identified what these are Tumor proteins They are able to stimulate the immune system at any stage of the disease process – so-called neoantigens. In this way, they developed a molecular clock to understand tumor diversity and identify possible targets for future treatments.
“By diving deeper into these tumor proteins, we found one Mutation in the p53 gene This is particularly interesting because it activates the immune system against the tumor. This mutation could be the basis for the development of future therapeutic vaccines aimed at patients with triple-negative breast cancer who have this genetic alteration,” says De la Iglesia.
Cancer is a dynamic process and there are multiple mechanisms that evolve and converge, even within the same patient. This shows that the enemy we face is very intelligent.
However, the study results show that a single therapy is not enough. “Cancer is a dynamic process and there are multiple mechanisms that evolve and converge, even within the same patient. This shows that the enemy we face is very intelligent,” says De Mattos-Arruda.
“In addition, the molecular clock progresses at different rates in advanced stages, causing… Precision therapies are more difficult to apply. “Therefore, it is necessary to develop therapies that simultaneously block different immune evasion mechanisms and attack cancer from different sides,” he concludes.
Reference:
Blanco-Heredia, J. et al. “Converging and evolving immunogenomic pathways for immune escape in breast cancer.” Nature communication (2024).
The project was supported by Merck Research 2020 in Immuno-oncology and was carried out in collaboration with centers in Spain, the United Kingdom and the United States, including the National Center for Genomic Analysis, the Rosell Cancer Institute and the Memorial Sloan Kettering Cancer Center and the Cancer Research UK Cambridge Institute.