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Protein marker helps predict mortality in patients with aggressive cancer

Caused by exposure to asbestos (asbestos), malignant pleural mesothelioma It is a rare but very aggressive type of cancer, with a survival prognosis of six to 18 months, which makes it necessary to identify new predictive and prognostic markers for the disease.

At work published in the journal Frontiers in Immunology, pathologists from the Faculty of Medicine of the University of São Paulo (FM-USP) suggest that the expression of a molecule called mesothelin (a protein synthesized by mesothelioma tumor cells) helps to predict the patient's clinical evolution. And, furthermore, that the protein would be a potential therapeutic target.

“There are several other therapeutic targets, but this protein has been a very promising candidate, the 'apple of the eye', both as a prognostic and predictive marker for the disease, but that's not all. By inhibiting it, we saw that it is possible to reduce cell proliferation and contain tumor growth”, he reveals. Vera Luiza Capelozzi one of the authors of the article.

She explains that exposure to asbestos fibers destroys normal mesothelial cells in the pleura, the membrane that lines the lung. The disease develops from the combined effect between pleural cells and macrophages (defense cells) that phagocytose asbestos fibers.

“Asbestos is a silicate that has a structure similar to that of a crystal. When asbestos fiber is inhaled, the macrophage, our main defense cell, phagocytoses this fiber, but is unable to destroy it. Over time, recurrent inflammatory reactions occur. Surrounding this macrophage are normal pleural cells. Over the years, mesothelial cells that have had contact with this fiber-bearing macrophage can proliferate without control and, in one of these divisions, can transform into neoplastic cells.”

The disease remains latent for a period of time and usually appears after the age of 50. It affects more men than women, mainly workers or former employees of companies that used or use asbestos in materials such as water tanks, tiles, linings, floors and partitions.

The World Health Organization (WHO) issued warnings about asbestos, classified as known to be carcinogenic and banned in several countries, including Brazil, which only banned it in 2017, after years of pressure from victims of diseases caused by the material, including pleural mesothelioma. Since then, often gathered in associations, those affected have been suing employers.

“This tumor has several implications and one of them is legal. By signing a malignant mesothelioma report, a frontier is opened to help the oncologist, the surgeon, but also to support labor processes. It’s a field on which you need to be very firm”, comments the researcher.

Favorable microenvironment

The team confirmed the importance of mesothelin – as a biomarker and as a promising target in the treatment of mesothelioma – and also examined its relationship with the immune system in the setting of the tumor microenvironment.

“Our idea from the beginning was to evaluate the tumor microenvironment and not gene expression. Because, if the tumor microenvironment is not favorable, the tumor cell does not progress. This scenario is important for the cell to move, invade and implant itself in other organs.”

In the search for a promising treatment for the disease, scientists investigated the protein expression of mesothelin and factor programmed cell death ligand 1 (PD-L1), a checkpoint protein (checkpoint) immune system that regulates the defense response and prevents autoimmunity (the attack on healthy tissues).

“PD-L1 is our immunological sentinel, it controls the production of autoantibodies by the body. The expression of PD-L1 and mesothelin by the tumor creates a functional barrier against malignant cells, inhibiting their migration and restoring the immunological scenario”, says Capelozzi.

The team of scientists showed that mesothelin remodels the immune matrix of the tumor microenvironment, recruiting different types of cells from the immune system and increasing type I collagen, which contributes to the establishment of an anti-tumor mechanical barrier, mitigating the risk of death.

Scientists also confirmed the potential of mesothelin as a biomarker, as they demonstrated that the risk of death was three times higher among non-operated patients with low expression of mesothelin in tumor cells, high levels of PD-L1 and low infiltration of lymphoid cells CD4+ T cells (involved in several immunological responses) in the tumor microenvironment.

Promising protocol

To select the sample, a retrospective survey was carried out using surgical samples and biopsies from patients with mesothelioma obtained in partnership with the Heart Institute (InCor) of Hospital das Clínicas (Pathological Anatomy Laboratory), São Paulo Cancer Institute (Icesp) and Hospital das Clínicas of FM-USP. The work was supported by FAPESP through three projects (18/20403-6 , 22/06510-0 It is 23/02755-0 ).

Of the 246 cases initially selected, 82 samples were included in the study. Patient data, including sex, age, history of asbestos exposure, histology, treatments performed and survival time, were collected.

Scientists have built microarrays (microarrays) of tissues from the 82 samples on slides and conducted immunohistochemistry and immunofluorescence assays. “Using mesothelin and PD-L1, we carried out the antigen-antibody reaction in the tumor tissue to detect the expression of biomarkers. When a fluorogen is added [substância fluorescente]mesothelin takes on a brownish color,” says the scientist.

The slides prepared by the researchers were also scanned in a special scanner. To quantify the expression of different markers, the digitized slides were analyzed using software called QuPath. According to the intensity of color assumed by mesothelin, it was possible to know whether it is overexpressed, underexpressed or negative.

“With this work, we were able to demonstrate that mesothelin is important in the tumor microenvironment and that, aligned with PD-L1, it could represent a promising therapeutic protocol. We are progressing with studies to analyze the relationship between mesothelin and PD-L1 with the microenvironment, evaluating collagen and elastic fiber, fibrillar components of the extracellular matrix that allow the cell to migrate and overcome the mechanical barriers that the organism creates to prevent the tumor cell enters the circulation and implants itself in other locations, causing metastasis”, summarizes Capelozzi.

The article Mesothelin expression remodeled the immune-matrix tumor microenvironment predicting the risk of death in patients with malignant pleural mesothelioma can be read at: www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2023.1268927/full .

Source: CNN Brasil

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