How to overcome the mechanism of treatment resistance in one of the most aggressive forms of breast cancer

The microenvironment surrounding HER2+ breast cancer tumors protects them and helps them develop resistance to the most widely used treatment, the monoclonal antibody trastuzumab
.
There is a special type of cell in this microenvironment, fibroblasts, that plays a key role
in this process.
These cells have the ability to stop the immune system, which protects the tumor
.
Finding ways to overcome this deficiency could improve the ability of treatments to
kill tumor cells.

Specifically, it is the presence of TGF - β-activated fibroblasts, which express a molecule called FAP that protects tumors from the action of
immune cells.
Trastuzumab is able to target cancer cells with high levels of the HER2 protein, and when it binds to cancer cells, it activates a strong immune response, which is the main reason why
it is effective against tumors.
However, in many tumors, the immune system is unable to break through the microenvironment around the tumor to clear the tumor
.
This leads to treatment resistance and increases the ability of this type of cancer to
evade drugs and spread further.
The mechanism was discovered by a team of researchers from the Imim Hospital Del Mar and the CIBER Cancer Research Center (CIBERONC) in a study published in the journal Nature Communications
.

The authors also found a way to overcome the tumor's ability to protect itself and allow the immune system to act
on the tumor cells.
Using an in vitro model, one that includes living cells from breast cancer patients, the researchers have shown that this ability to block immune cell access can be reversed
by targeting fibroblast-expressed FAP molecules through immunotherapy.
Dr Alexandre Calon, senior author of the study and head of the Tumor Microenvironment Translational Research Laboratory at the Hospital Delmarimm, said: "When this molecule, FAP-IL2v, is added to a reconstructed tumour containing this resistant microenvironment in vitro and comes into contact with immune cells, the effectiveness of trastuzumab is restored
.
"

The study validated the results
on three cohorts of patients and more than 120 samples.
In all these experiments, the level of activation of fibroblasts was found to be directly related
to the immune system's ability to act on tumors.
Although trastuzumab has an effect, the higher its level, the more difficult it is to access and eliminate tumor cells
.
Dr.
Calon emphasized that this helps to better select patients who will benefit from FAP-IL2v therapy, which is designed to invalidate
the effects of the tumor microenvironment.
"If we screen patients based on these characteristics, we can isolate a group of drug-resistant patients who can be targeted by this molecule to restore the effectiveness of
breast cancer treatment," he explains.

Dr.
Joan Albanell, director of oncology at del Mar Hospital, director of the cancer research program at IMM-del Mar Hospital and co-author of the study, noted that there are already drugs available to achieve this effect, but further studies must be conducted to evaluate their use in
patients.
"This study identified tumors resistant to anti-HER2 treatment primarily caused by one type of fibroblast and not other causes
.
This important finding should be used to design clinical trials that use drugs to overcome this resistance, only for those patients
with this resistance.
That's where we need to move towards precision oncology," adds
Dr.
Albanell.

The work was carried out in collaboration with researchers from the Barcelona Institute of Biomedical Sciences (IRB) and the Institute of Bioengineering of Catalonia (IBEC), as well as the INCLIVA Institute of Health in Valencia, with the support of the Cellex Private Foundation, the Carlos III Institute of Health and the
Spanish Association against Cancer.

The application of immunotherapy is one of the strategic lines of
ongoing cancer research at IMM Hospital Del Mar.
Several projects are currently underway with very encouraging results aimed at validating ways to improve efficacy or identifying new ways
to promote their application.