Study determines the role fibroblasts play in the tumor's ability to generate resistance to HER2 therapy

Study determines the role fibroblasts play in the tumor's ability to generate resistance to HER2 therapy

A study led by researchers at the Hospital del Mar Medical Research Institute (IMIM-Hospital del Mar) has determined the role that fibroblasts, the cells that contribute to tissue formation, play in a tumor's ability to generate resistance to the most common biological treatments HER2.

The paper, published in the journal Nature Communications, demonstrates the ability of a new therapy currently in clinical testing to promote a strong immune response by binding to the fibroblasts, thus overcoming resistance to anti-HER2 therapy in tumors with this cancer cell protection mechanism. To demonstrate this, the researchers created a 3D tumor model in which they could examine the relationships between all the factors involved.

HER2+ breast cancer is one of the most aggressive and rapidly progressing cancers. HER2-targeted treatments have changed the outlook, but resistance continues to hamper the potential for cure.

Research into resistance to cancer treatments is yielding very encouraging results thanks to projects led by researchers from the IMIM-Hospital del Mar cancer research program.

The microenvironment surrounding tumors in HER2-positive breast cancer protects them and helps them develop resistance to the most widely used treatment, the monoclonal antibody trastuzumab. And a specific cell type in this microenvironment, fibroblasts, plays a key role in this process. These cells have the ability to block the immune system and thereby protect the tumor. Finding a way to overcome this increases the treatment's ability to kill tumor cells.

In particular, it is the presence of TGF-beta-activated fibroblasts that express a molecule called FAP that protects the tumor from the action of immune cells. Trastuzumab has the ability to attack cancer cells that have high levels of the HER2 protein, and when it binds to cancer, it activates a strong immune response that contributes significantly to its effectiveness against the tumor. However, in many tumors, the immune system is unable to break through the microenvironment surrounding the tumor to eliminate it. This leads to treatment resistance and increases the ability of this type of cancer to evade the drug and continue to multiply. This mechanism was discovered by a team of researchers from IMIM-Hospital del Mar and 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 ex vivo model, that is, a model containing live cells from breast cancer patients, the researchers have shown that by targeting the fibroblast-expressed FAP molecules with immunotherapy, this ability to prevent immune cell access can be reversed. “When this molecule, FAP-IL2v, is given to an ex vivo recreated tumor containing this treatment-resistant microenvironment in contact with immune cells, the effectiveness of trastuzumab is restored,” explains Dr. Alexandre Calon, senior author of the study and head of the Translational Research in Tumor Microenvironment Laboratory at IMIM-Hospital del Mar. It should be noted that the model generated uses human cells and is also applicable to other types of tumors.

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The study validated the results with three cohorts of patients and more than 120 samples. In all, the extent of fibroblast activation was found to be directly related to the ability of the immune system to act on the tumor. The higher the values, the more difficult it is to reach and eliminate tumor cells, despite the effect of trastuzumab. Dr. Calon emphasized that this facilitates better selection of patients who would benefit from FAP-IL2v treatment, which aims to deactivate the effect of the tumor microenvironment.

If we filter out people based on these characteristics, we can isolate a population of treatment-resistant patients who can be targeted with this molecule to restore the effectiveness of breast cancer therapy.”

Dr. Alexandre Calon, senior author

Drugs that can achieve this effect are already available, although further studies need to be carried out to evaluate their use in patients, according to Dr. Joan Albanell, head of the oncology department at Hospital del Mar, director of the cancer research program at IMIM-Hospital del Mar and co-author of the study, emphasized. "The study identifies tumors in which anti-HER2 therapy resistance is primarily caused by one type of fibroblast and not by other causes. This important discovery should be used to develop clinical trials with drugs that overcome this resistance only for those patients in whom this resistance is present. Here we need to move towards precision oncology," adds Dr. Albanell added.

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

Cancer immunotherapy at IMIM

The application of immunotherapy is one of the strategic lines of cancer research carried out at IMIM Hospital del Mar. Several projects are currently underway with very encouraging results, aimed at validating ways to increase effectiveness or identifying new approaches to facilitate their application.

Source:

IMIM (Medical Research Institute of the Hospital del Mar)

Reference:

Rivas, E.I., et al. (2022) Targeted immunotherapy against specific cancer-associated fibroblasts overcomes treatment resistance in refractory HER2+ breast tumors. Nature communication. doi.org/10.1038/s41467-022-32782-3.

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