Spanish scientists discover key to aggressive 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 follow-up was unique both in terms of observation time 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.

The patient’s follow-up was unique in both the length of follow-up and the number of samples and parameters studied.

Leticia De Mattos-Arruda
— IrsiKaisha

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 manages to fight cancer at each stage of the disease and what mechanisms make it so that later the defense cannot defeat it,” emphasizes 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. One of these patients could be followed from diagnosis, progression of metastases, and until death.

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

The study included 112 samples from 12 patients with metastatic triple-negative breast cancer, including primary tumors and metastases present during the course of the disease and at autopsy.

Filtering this data revealed that genetic and immune variability both within each tumor and between different metastases is very large, and that some of these genetic changes give cancer cells the ability to evade the body’s defenses.

The mechanisms by which cells avoid them are varied, from preventing the production of inflammatory molecules that attract immune cells to the tumor, to hiding tumor proteins that are recognized by the defense system.

More importantly, however, the study shows that all of these mechanisms act simultaneously and in synergy within the same tumor, leading to disease progression despite the immune system’s constant 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 be the basis for the development of future therapeutic vaccines targeting patients with triple-negative breast cancer who have this genetic change,” says De la Iglesia.

Cancer is a dynamic process and there are many mechanisms that evolve and converge even within the same patient. This shows that the enemy we face is very smart.

Leticia De Mattos-Arruda

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

“Also, the molecular clock moves at different rates when we are in advanced stages, 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.

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.

Link: Blanco Heredia, J. and others – “Convergence and evolution of immunogenomic pathways to immune escape in breast cancer”. Magazine Natural communications, 2024 | DOI: 10.1038/s41467-024-45292-1.