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October 24, 2022Research led by a team from the Hospital del Mar Institute in Barcelona has determined the role of cells that contribute to tissue formation, fibroblasts, in the ability of tumors to generate resistance to the most common biological treatment directed against the protein. HER2.
The microenvironment surrounding tumors in HER2+ breast cancer protects them and facilitates the generation of resistance to the most used treatment against it, the drug trastuzumab, a monoclonal antibody. And in this process, a specific type of cell in this microenvironment, fibroblasts, plays a decisive role. These cells have the ability to block the immune system and thus the tumor is protected. Finding a way to overcome it enhances the treatment's ability to eliminate tumor cells.
Specifically, the presence of fibroblasts activated by TGF-beta, which express a molecule called FAP, is what protects the tumor from the action of immune cells. Trastuzumab has the ability to attack cancer cells that show high levels of the HER2 protein, and when it binds to the cancer, it activates a strong immune response, which greatly contributes to its effectiveness against the tumor.
Despite this, in many tumors, the immune system is not able to penetrate the microenvironment surrounding the tumor and eliminate it. In this way, resistance to treatment is generated and the ability of this type of cancer to evade the drug and proliferate again increases. A mechanism that the team of researchers from the IMIM-Hospital del Mar and the CIBER del Cancer (CIBERONC) have been able to discover, in a study published by the Nature Communications magazine.
The work has also identified a way to overcome this ability of the tumor to protect itself and open the door to the immune system to act on tumor cells. Using an ex vivo model, that is, a model that allows working with living cells from breast cancer patients, the authors of the study have proven how by marking the FAP molecule expressed by fibroblasts with immunotherapy, their ability to prevent the access of the immune cells.
Model applicable to other types of tumors
“When this molecule, FAP-IL2v, is added to an ex vivo recreated tumor that contains this treatment-resistant microenvironment, in contact with immune cells, the effectiveness of trastuzumab is restored,” explained Alexandre Calon, lead author of the research and responsible for the Translational Research Laboratory in Tumor Microenvironment of the IMIM-Hospital del Mar. It should be noted that the model that has been generated uses human cells and is also applicable to other types of tumors.
The study has validated the results with three cohorts of patients, with more than 120 samples. In all of them it has been possible to verify how the activation levels of fibroblasts have a direct relationship with the ability of the immune system to act on the tumor. At higher levels, more difficulty in accessing and eliminating tumor cells despite the action of trastuzumab.
Calon has highlighted that this allows us to better select patients who will benefit from treatment with FAP-IL2v aimed at deactivating the action of the tumor microenvironment. “If we filter patients based on these characteristics, we can isolate a population of treatment-resistant patients who can be treated with this molecule and restore the effectiveness of breast cancer treatment,” he noted.
At this time there are already drugs that can be used to achieve this effect, "although more studies will still have to be carried out to evaluate their application in patients, as indicated by Joan Albanell, head of the Oncology Service at Hospital del Mar. director of the Cancer Research Program at IMIM-Hospital del Mar and co-author of the study.
According to Albanell, “the study identifies tumors in which resistance to anti-HER2 therapy is caused mainly by a type of fibroblasts and not by other causes. This important discovery should serve to design clinical trials with drugs that overcome this resistance only for those patients in whom this resistance is operative. “It is where we have to go in precision oncology.”
The work has had the collaboration of researchers from the Institute of Biomedical Research of Barcelona (IRB) and the Institute of Bioengineering of Catalonia (IBEC), as well as the INCLIVA Health Research Institute of Valencia and with the support of the Cellex Private Foundation, from the Carlos III Health Institute and the Spanish Association against Cancer.
Source: Sync. Reference: Rivas, EI, Linares, J., et al. “Targeted immunotherapy against distinct cancer-associated fibroblasts overcomes treatment resistance in refractory HER2+ breast tumors.” Nat Commun (2022).