3D image of breast cancer metastasizing representing HER2 breast cancer.
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Researchers at the Hospital del Mar medical research institute (IMIM) in Barcelona, Spain have discovered how to overcome a treatment resistance mechanism in one of the most aggressive types of breast cancer by activating the body’s immune response.

HER2 positive breast cancer tends to grow faster, spread and recur more often than other types of the disease. In addition, the tumors are surrounded by a microenvironment, protecting and enabling them to develop resistance to antibody treatments such as trastuzumab, which normally allows immune cells to eliminate the cancer. Cells called fibroblasts play a key role in this process by blocking the immune system trying to attack the tumor. A team of researchers at IMIM is now trying to target these cells to overcome resistance.

Reporting in Nature Communications, the scientists identified a specific type of fibroblasts called TGF-beta-activated fibroblasts, which express a molecule called FAP, protecting the tumor from immune cells. Using an ex vivo model, including cells from breast cancer patients and trastuzumab as the treatment, the researchers targeted FAP molecules using another molecule called FAP-IL2v, showing that resistance towards the immune cells can be reversed.

“When this molecule, FAP-IL2v, is added to a tumor recreated ex vivo that contains this treatment-resistant microenvironment, in contact with immune cells, trastuzumab’s effectiveness is restored,” said Alexandre Calon, PhD, head of the translational research in tumor microenvironment laboratory at the IMIM, and senior author of the study in a press statement.

The researchers validated the results with three cohorts of patients using over 120 samples. According to the study, in all samples the number of activated fibroblasts directly affected the immune system’s ability to attack the tumor. The higher the levels of fibroblasts, the harder it was for immune cells to target the cancer cells despite antibody treatments such as trastuzumab activating the immune system.

Senior author Calon stated that this enables a better selection of patients who will benefit from FAP-IL2v treatment designed to deactivate 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 the breast cancer therapy,” Calon explained.

Other approaches at modifying the tumor microenvironment to improve the efficacy of drug delivery exist. A previous review article published in Trends in Cancer discusses the possibilities of reengineering the physical tumor microenvironment such as targeting the blood vessels surrounding a tumor in an attempt to deplete the cancer cells of oxygen and nutrients effectively eliminating them.

Concluding in a press statement, co-author of the IMIM study Joan Albanell, PhD, head of the oncology department at IMIM said that “The study identifies tumors in which anti-HER2 therapy resistance is caused primarily by one type of fibroblast rather than other causes. This important discovery should be used to design clinical trials with drugs that overcome this resistance only for those patients in whom this resistance is operative. This is where we need to move towards precision oncology.”

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