Spanish researchers have managed to transform tumors resistant to immunotherapy into vulnerable to this treatment and have achieved cures in mice through an innovative therapeutic strategy in triple negative breast cancer, the most aggressive subtype.
Triple negative breast cancer represents only 15% of cases, but it is one of the fastest growing cancers and affects younger patients.
The work, published today in the journal Nature Cancer, has used an innovative experimental messenger RNA system, similar to the technology used in vaccines against COVID-19, to produce a factor, the LCOR gene, in tumor cells and which is make them visible and sensitive to the immune system.
Researchers at the Hospital del Mar Medical Research Institute (IMIM) and the Hospital del Mar in Barcelona (northeast Spain) have discovered that tumor stem cells are the main cause of resistance to immunotherapy in this subtype of breast cancer because they are invisible to the immune system, and this makes immunotherapy not work.
This subtype of breast cancer has low levels of the LCOR factor, which plays a key role, hitherto unknown, for cells to present antigens on their surface, molecules that allow the immune system to differentiate normal cells from tumor cells and attack to the latter.
In the case of tumor stem cells, the low presence of this LCOR factor makes them invisible to the body’s defenses and resistant to immunotherapy.
“This ability of tumor stem cells to remain invisible to the immune system allows them to survive treatment with immunotherapy”, explains Toni Celià-Terrassa, who leads the Laboratory of Cancer Stem Cells and Dynamics of Metastasis.
The researcher details that they have verified how, “despite treatment with immunotherapy, these cells survive and have the ability to generate resistance, a fact linked to their ability to hide from the immune system, which allows them to evade immunotherapy.”
Using laboratory mice, the scientists verified how this situation was reversed when the LCOR gene was activated in this type of cell and the machinery to be detected by the immune system was activated.
“It is about reconfiguring the tumor to make it fully visible and, therefore, sensitive to immunotherapy, going from invisibility to visibility,” says Iván Pérez-Núñez, an IMIM researcher.
The scientists have also verified how, by combining this approach with immunotherapy, the response rate to the treatment was total and all the tumors were eliminated, curing the mice in the long term, which, according to the doctors, would make it possible to prevent the recurrence of the cancer and the generation of resistance.
For their study, they used a strategy inspired by the technology used for messenger RNA vaccines against COVID-19 to transport and introduce RNA from the LCOR gene into tumor cells and activate its function.
The researchers developed biological nanovesicles, small bag-shaped structures formed in cells, to transfer this information and verified that they did so successfully, preventing the invisibility of tumor stem cells.
“What we are doing is that the immune system sees the tumor cell better. Unlike healthy cells, malignant cells have a much higher load of recognized foreign antigens, not those of the immune system. In this way, the natural defenses of the body will recognize, attack and eliminate malignant cells”, sums up Celià-Terrassa.
This strategy may be applicable to other types of tumor, although safety studies and clinical trials in humans will have to be carried out beforehand. (I)
Source: Eluniverso
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