Nat Commun: Scientists are expected to overcome the molecular mechanisms by which breast cancer tolerance to therapy occurs

Scientists from institutions such as the Spanish Cancer Network's Biomedical Research Center have revealed the molecular mechanisms
behind these processes.

The microenvironment surrounding HER2+ breast cancer may protect tumors and help them develop tolerance to trastuzumab, a widely used therapy, and special types of cells in the tumor microenvironment called fibroblasts play a key role in this process, blocking the function of the immune system and protecting tumors, and finding a way to overcome this situation may enhance the ability of
new therapies to kill tumor cells 。 Specifically, it is the presence of TGF-β-activated fibroblasts that expresses a molecule called FAP, thereby protecting tumors from the action of immune cells, and the drug trastuzumab can target cancer cells expressing high levels of HER2 protein, and when it binds to cancer, it can also activate the body's strong immune response, which is a major contributor to the efficacy of
anti-tumors.

However, in many tumors, the immune system is unable to break through the microenvironment around the tumor to destroy the cancer, which leads to the development of the cancer's tolerance to therapy and increases the cancer's ability to
evade drugs and further proliferate 。 Recently, a research report published in the international journal Nature Communications entitled "Targeted immunotherapy against distinct cancer-associated fibroblasts overcomes treatment resistance in refractory HER2+ breast tumors", Scientists from institutions such as the Spanish Cancer Network's Biomedical Research Center have revealed the molecular mechanisms
behind these processes.

In the article, the researchers identified a new way to overcome how tumors protect themselves and allow the immune system to act on tumor cells, using an in vitro model that includes living cells from breast cancer patients, and the researchers found that by using immunotherapy to target FAP molecules expressed by fibroblasts, the ability of tissue immune cells to enter may be reversed
。 Dr.
Alexandre Calon said that when the FAP-IL2v molecule is added to reconstructed tumors in vitro containing the microenvironment tolerated by this therapy, the potency of trastuzumab is restored when in contact with immune cells; It should be noted that the model developed by the researchers can use human cells and is equally applicable to other types of tumors
.

Scientists are expected to overcome the molecular mechanisms by
which breast cancer develops resistance to therapy.

Image source: Nature Communications (2022).
DOI:10.
1038/s41467-022-32782-3

In this study, the researchers validated the results by studying 3 patient cohorts and more than 120 samples, and in all samples, the level of fibroblast activation was directly related to the immune system's effect on the tumor, that is, the higher the level, the more difficult it was to access and eliminate tumor cells (although trastuzumab played a role), which the researchers emphasize may be beneficial to help select patients who can benefit from FAP-IL2v therapy, which is designed to relieve the effect on the tumor microenvironment
。 The researchers explain that if we can screen the population based on these characteristics, we can select patient populations that are resistant to therapy, and researchers can use special molecules to target them to restore the therapeutic effect
of breast cancer therapy.
There are already drugs that can achieve this effect, although more research is needed to evaluate its use
in patients.

Researcher Albanell said: "The study identified that tumors resistant to HER2 therapy may be triggered primarily by a type of fibroblast rather than other causes, and this important finding may be used to design clinical trials that use drugs to overcome this tolerance and only target resistant patient groups, which may be the direction researchers need to develop towards precision oncology
.
In summary, the results of this study highlight the potential of harnessing the tumor microenvironment to identify and overcome the molecular mechanisms of
the body's tolerance to anticancer therapy.
(Bio Valley Bioon.
com)

Original source:

Rivas, E.
I.
, Linares, J.
, Zwick, M.
 et al.
 Targeted immunotherapy against distinct cancer-associated fibroblasts overcomes treatment resistance in refractory HER2+ breast tumors.
 Nat Commun 13, 5310 (2022).
doi：10.
1038/s41467-022-32782-3