Pilar Pérez Madrid
Madrid
Updated Wednesday, January 24, 2024-11:10
Know the enemy.
That's what scientists do when they design their weapons to kill cancer.
Sometimes it's difficult.
So, finding their weaknesses and the responses to the cells' reactions is key.
When oncological treatments
are applied,
the annihilation of the tumor units is pursued, but they do not always 'die completely'.
Sometimes they remain in a
zombie
state .
They do no harm, nor do they generate more carcinogenic armies.
But they prevent the area of the neoplasia from being accessed and cleaned.
In reality,
these cells are called senescent
and
create an environment hostile to targeted therapies
, by hindering the defenses, the immune system, from accessing the tumor.
The
effectiveness of chemotherapy increases when 'zombie' or senescent cells are prevented from deactivating the immune system
.
This is the conclusion of a work by a group of researchers from IRB Barcelona.
In the publication revealed today by the journal
Nature Cancer,
they describe a mechanism by which senescent cells generated by chemotherapeutic treatments survive inside tumors.
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In the laboratory launched by researcher Manuel Serrano at IRB Barcelona, they have
successfully demonstrated a new therapy in animals that eliminates senescent cells
and improves the effectiveness of chemotherapy.
"What we have done is
use our own immune system to kill them
," explains José Alberto López, postdoctoral researcher at the same laboratory and first author of the work.
As?
Activating the body's defenses, but through a route that until now was not considered important: the PDL2 protein.
"Senescent cells have a membrane that inhibits the immune system. When chemotherapy is applied to them, the immune system stops functioning correctly," explains López.
Zombie cells are like a kind of firewall that prevents treatments from accessing the tumor.
That is,
senescent cells
act as suppressors and develop an environment in which lymphocytes, the defenses, are prevented from accessing and acting against cancer cells.
In this way, senescent cells
promote tumor growth and limit the effectiveness of chemotherapy
.
Senescent human melanoma tumor cells.
In brown, the PD-L2 protein that acts as a protective shield and prevents the action of the immune system.IRB Barcelona
The solution, "edit the PDL2 protein."
In this way, "the immune system can eliminate both senescent and tumor cells, since the former protect the latter," points out the author of the study.
Until now, the PDL1 protein had a more active role, because it is well studied and is one of the targets against which therapeutic strategies have been designed.
It is the target of most immunotherapy treatments.
"Meanwhile,
we assumed that the PDL2 had a similar role and did not contribute anything additional
," says López.
As Serrano summarizes, "by blocking PD-L2 we have seen in mouse models that chemotherapy is more effective against cancer. This opens the way to considering
the use of a potential PD-L2 inhibitor as an adjuvant in the treatment of this disease
."
Currently, the researcher participates in research from his position at Altos Labs (Cambridge, United Kingdom).
For now, the work has been validated in cell lines and with animal research models of skin, pancreatic and breast cancer.
"We have to see how we translate it into trials that provide answers for use in clinical practice," López emphasizes.
The research has had the
support of the Spanish Association Against Cancer
.
In addition, it has been carried out in collaboration with the groups of doctors Joaquín Arribas, Alena Gros and María Abad at the Vall d'Hebron Institute of Oncology (VHIO).
Arribas also directs the Hospital del Mar Research Institute (IMIM) and Abad works at Altos Labs. The team led by James Kirkland and Tamara Tchkonia from the Mayo Clinic have contributed important data to this study.
The company Rejuveron Senescence Therapeutics, with offices in Zurich and Barcelona, which is clinically developing antibodies against PD-L2, has also participated in the work.
Next step: human trials
After
finding the 'key' to turn off the firewall
that zombie cells represent, López explains that "we must find a way to identify senescent cells in tumors."
Senescence derived from antitumor treatments is not exclusive to one type of tumor.
"We have
biological markers
that allow us to determine the presence of senescent cells, such as P16 and P21," says López.
The researcher hopes that they will find a way to find them
without it being an invasive test
for the patient.
"We can observe them through the tissues that are biopsied," but, López insists, "this makes the patient uncomfortable."
For this reason, they hope to develop effective mechanisms through
liquid biopsy,
which is a blood test, or "through the
high-resolution images
that we can obtain with resonance."
Senescence, a key area of study
The processes of cellular senescence and their implications for longevity have been studied for years.
In itself, it is a phase that occurs naturally in aging and has emerged as a common phenomenon in the context of cancer therapies.
Currently, most oncological therapies, such as chemotherapy or radiotherapy, act by causing multiple cellular damage and, as a consequence, cause senescent cells, particularly within the tumor.
The scientific team will now study whether senescence linked to the aging of the organism is also correlated with elevated levels of PD-L2.
A year ago, the Serrano team also presented senescent cells as a window of opportunity to "stimulate the immune system against cancer, and open the way to considering vaccination with these cells as a possible therapy," as Serrano pointed out, in an IRB statement following the publication of the advance in the journal
Cancer Discovery
.