Researchers Discover How To Overcome A Treatment Resistance Mechanism In One Of The Most Aggressive Types Of Breast Cancer: ScienceDaily

The microenvironment around tumors in HER2 + breast cancer protects them and helps them develop resistance to the most widely used treatment, the monoclonal antibody trastuzumab. And a particular type of cell 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 problem increases the treatment’s ability to kill cancer cells.

Specifically, it is the presence of fibroblasts activated with TGF-beta, which express a molecule called FAP, which protects the tumor from the action of immune cells. Trastuzumab has the ability to target cancer cells with high levels of the HER2 protein and, when it binds to cancer, triggers a strong immune response, which contributes significantly to its efficacy against cancer. However, in many cancers, the immune system is unable to break through the microenvironment surrounding the tumor to eliminate it. This leads to resistance to treatment and increases this type of cancer’s ability to evade the drug and proliferate further. This mechanism was discovered by a team of researchers from IMIM-Hospital del Mar and the CIBER Cancer Research Center (CIBERONC) in a study published in the journal Nature communications.

The authors also identified a way to overcome the tumor’s ability to protect itself and allow the immune system to act on the cancer cells. Using an ex vivo model, i.e. a model that includes living cells from breast cancer patients, the researchers demonstrated that by targeting FAP molecules expressed by fibroblasts with immunotherapy, this ability to prevent immune cells from entering can be reversed. “When this molecule, FAP-IL2v, is added to an ex vivo recreated tumor that contains this treatment-resistant microenvironment, in contact with the immune cells, the efficacy of trastuzumab is restored,” says Dr. Alexandre Calon, senior author of the research and head of the Translational Research in Tumor Microenvironment Laboratory at IMIM-Hospital del Mar. Note that the generated model uses human cells and is also applicable to other types of tumors.

The study validated the results with three patient cohorts and more than 120 samples. In all levels of fibroblast activation they were directly related to the immune system’s ability to act on the tumor. The higher the levels, the greater the difficulty in accessing and eliminating cancer cells despite the action of trastuzumab. Dr. Calon pointed out that this facilitates a better selection of patients who will benefit from the FAP-IL2v treatment aimed at deactivating the action of the tumor microenvironment. “If we filter 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,” he explains.

Drugs are already available that can be used to achieve this effect, although further studies are needed to evaluate their application in patients, says Dr Joan Albanell, head of the oncology department at Hospital del Mar, director of research on the Cancer Program at IMIM-Hospital del Mar and co-author of the study, points out. “The study identifies cancers in which resistance to anti-HER2 therapy is caused primarily by one type of fibroblast rather than other causes. This important finding should be used to design clinical trials with drugs that overcome this resistance only for those patients in where this resistance is operative. This is where we need to move towards precision oncology, “adds Dr. Albanell.

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

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Materials provided by IMIM (Medical Research Institute of the Ospedale del Mar). Note: The content can be changed by style and length.

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