They found out what factors contribute to the progression of triple negative breast cancer

AIDS Research Institute IrsiCaixa led the case study triple negative breast cancer which demonstrates how cancer cells are presented multiple genetic changesbut also protein and cellular processes that allow them to evade the body’s own defenses and immunotherapy.

The results were published in the journal Natural communications show that although immune reaction The fight against cancer remains persistent until the end of the disease, the genetic complexity of cancer cells and their ability to evade the immune system does not allow it to win.

“The patient’s observation was unique both in terms of the observation period and the number of samples and parameters studied. “We studied every corner of the tumor and the human immune system for more than 5 years,” he explains. Leticia De Mattos-Arrudaoncologist at IrsiCaixa at the time of the study, senior lead author of the paper, currently working at BioNTech.

Triple negative breast cancer This is one of the most aggressive and difficult to treat because it does not respond to classical treatments. However, immunotherapy is usually an option for these patients because they have many more mutations than others, making them visible to the immune system.

“We wanted to understand How the immune system fights cancer at every stage of the disease and what mechanisms make it so that in the future the defense will not be able to defeat it,” notes De Mattos-Arruda.

Mutation and immune system evasion

The study had 112 samples from 12 patients metastatic triple negative breast cancer, including primary tumors and metastases present during the course of the disease and at the time of autopsy. In the case of one of these patients follow-up is possible from the time of diagnosispassing through the progression of metastases, and even death.

“We examined sequential samples of blood, primary tumor and metastases using multi-omics methods that allow access to all information about genes, proteins and even the cellular composition of samples» indicates Nuria Church, co-author and researcher at IrsiCaixa. “The hardest part was getting all this huge amount of data and making sense of it.”

Filtering this data allowed us to see that genetic and immune variability within each tumor since between different metastases it is very largeand that some of these genetic changes give cancer cells the ability to evade the body’s defenses.

The mechanisms by which cells avoid them range from preventing the production of inflammatory molecules that attract immune cells to the tumor. until the tumor proteins recognized by the defense disappear.

More importantly, however, the study shows that these mechanisms All of them act simultaneously and synergistically within the same tumor.causing the disease to progress despite the immune system’s continued efforts to fight it.

Combined methods to combat it

The team determined which ones tumor proteins capable of stimulating the immune system (so-called neoantigens) at each stage of the pathological process. So they mapped the molecular clock to understand tumor diversity and identify possible targets for future treatments.

“As we delved deeper into these tumor proteins, we discovered mutation in the p53 gene which is particularly interesting because it activates tumor defense. This mutation could provide the basis for the development of future therapeutic vaccines intended for use in patients. who have triple negative breast cancer that represents this genetic change“, says De la Iglesia.

However, the study results show that therapy alone is not enough. “Cancer This is a dynamic process and there are many mechanisms that evolve and converge.even in the same patient. This shows that the enemy we face is very smart,” says De Mattos-Arruda.

“In addition, in later stages the molecular clocks move at different speeds, so precision therapy they are more difficult to apply. This is why it is necessary to develop treatments that simultaneously block different immune evasion mechanisms and attack cancer from different angles,” he concludes.

Link:

Blanco-Heredia, J. et al. “Convergence and development of immunogenomic pathways to immune escape in breast cancer.” Natural communications (2024).

The project was supported by Merck Research 2020 in Immuno-Oncology and in collaboration with centers in Spain, UK and USA, such as the National Center for Genomic Analysis, Roselle Cancer Institute, Memorial. Sloan-Kettering Cancer Center and Cambridge Cancer Research UK.