Study determines role of fibroblasts in tumor ability to induce 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 fibroblasts, thereby 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 check the connections between all the factors involved.

HER2+ breast cancer is one of the most aggressive and rapidly progressive types of cancer. HER2-targeted treatments have changed the outlook, but resistance continues to impede the potential for healing.

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 will increase 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 powerful immune response that is a major contributor to its anti-tumor efficacy. 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 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 communication.

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, ie a model containing living cells from breast cancer patients, the researchers showed that by targeting the fibroblast-expressed FAP molecules with immunotherapy, this ability to prevent immune cell access, can be undone. “When this molecule, FAP-IL2v, is placed in contact with immune cells in an ex vivo replicated tumor that contains this treatment-resistant microenvironment, the efficacy 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 tumor types.

The study validated the results using three cohorts of patients and more than 120 samples. In all, the level of fibroblast activation was found to be directly related to the ability of the immune system to target 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 would facilitate better selection of patients who would benefit from FAP-IL2v treatment aimed at disabling the effects of the tumor microenvironment.

If we screen people based on these traits, we can isolate a population of treatment-resistant patients who can be targeted with this molecule to restore efficacy to breast cancer therapy.”

dr Alexandre Calon, senior author

Drugs are already available that can achieve this effect, although more studies need to be done to evaluate their use in patients, says Dr. Joan Albanell, head of the department of oncology at Hospital del Mar, director of the cancer research program at IMIM-Hospital del Mar and co-author of the study, stressed. “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 of drugs that overcome this resistance only for those patients who have this resistance. This is where we need to move towards precision oncology,” adds Dr. Albanell.

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) and the INCLIVA Health Research Institute in Valencia and with the support of 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.