A research team, formed by José Ignacio Rodríguez-Barbosa and María Luisa del Río, has developed monoclonal antibodies and recombinant proteins which have a fundamental function in the immunotherapy of tumours.

The Immunobiology and Transplantation group at the University of León (ULE), made up of professors José Ignacio Rodríguez-Barbosa and María Luisa del Río González, has been working for more than two decades on modulating the exchange of signals that allow communication between antigen-presenting cells and T cells, in order to decrease or increase the immune response.

To address this objective, this team develops monoclonal antibodies and recombinant proteins, the latter acting as decoys, allowing the interruption of the interaction between the molecular ligands expressed in the antigen-presenting cells and the enhancer or inhibitory receptors of the T cells.

In this way, they explain that the immune response can be depressed in transplantation or increased in the case of wanting to enhance our defense systems against cancer.

“This set of therapeutic interventions is part of the new generation of biological drugs, the study of which is part of the branch of immunology known as immunotherapy. This therapy uses the individual's immune system by stimulating its own defenses to combat cancer or infections by pathogenic microorganisms,” they emphasise.

Different types of immunotherapy may include active immunotherapy based on cancer vaccines and passive immunotherapy, which consists of the administration of monoclonal antibodies against specific markers of tumour cells or molecules that act as inhibitors of immune system checkpoints, as well as recombinant proteins that block molecular ligand/receptor interactions.

"In addition," says Del Río González, "cellular immunotherapy is based on the use of genetically manipulated T cells to express a chimeric antigen receptor." "Essentially," explains Rodríguez-Barbosa, "these are T lymphocytes that are modified through genetic engineering to express an antibody molecule coupled to a T cell activation system that, upon locating the cancer cell, is capable of destroying it. Very effective in the treatment of hematopoietic tumours.”

Along these lines, he comments that the immune system's checkpoints function as "response brakes" and "are essential" in maintaining tolerance to the immune system, preventing autoimmunity, as well as controlling the duration and extent of the immune response, with the goal of minimising collateral tissue damage.

"The ligands that control these immune system checkpoints are frequently overexpressed in tumour cells or in non-transformed cells within the tumour microenvironment itself and compromise the immune system's ability to develop an effective antitumour response," he adds.

Among the best studied checkpoint inhibitors, the PD-1/PD-L1 and CTLA-4/B7-1/B7-2 interactions stand out. The expression of PD-L1 in the tumour prevents anti-tumour T cells from destroying the tumour, since they are capable of inhibiting its function through the co-inhibitory receptor PD-1.

Blocking the binding of PD-L1 to PD-1 with an immune checkpoint inhibitor such as monoclonal antibodies directed against PD-L1 or PD-1 allows T cells to overcome the inhibition induced by the tumour and, therefore, can be recognised and eliminated.

In this regard, in 2010 the first monoclonal antibody directed against the immune checkpoint CTLA-4 (Ipilimumab) was approved by the United States Food and Drug Administration (FDA) for the treatment of melanoma. Later, the FDA approved two treatments targeting the PD-1/PDL1 signaling pathway.

In line with the above, these ULE researchers are working to identify and validate new groups of molecules as therapeutic targets that the tumour uses to inhibit defenses and that allow them to evade the anti-tumour response and colonize the individual through the feared metastasis.

As the researchers recognise, monoclonal antibodies and soluble recombinant proteins constitute the most innovative biological drugs in current medicine for the treatment of numerous inflammatory diseases and in cancer therapy.

Depending on the biological activity, María Luisa del Río González says that they can be used to enhance the immune response, as in the case of cancer treatment, or, on the other hand, to reduce it, as in immunotherapy for organ rejection.

With these tools and the help of preclinical murine models of disease, cell or tissue transplants and the use of transplantable tumour cell lines, they can recreate the human disease to study it in the laboratory and thus find new innovative treatments that can be applied to humans, once the corresponding clinical trials of efficacy, safety and toxicity have been completed.

In the article published in the biomedical journal Frontiers in Immunology, they have eliminated the expression of the PD-L1 molecule in a transplantable tumour line that serves as a model for a lymphoid hematopoietic tumour.

The contribution of natural killer cells to tumour rejection in the context of the PD-1/PDL1 interaction has been the subject of enormous scientific debate in recent years.

To elucidate the role of PD-L1 expression in tumour cells and to understand the consequences of its binding to its PD-1 receptor in cytotoxic cells (natural killer cells and CD8 T lymphocytes), the researchers from León generated a PD-L1-deficient tumour line by applying CRISPR/Cas9 technology.

In this way, they were able to compare the behavior of control tumour cells that express PD-L1 versus PD-L1-deficient tumour cells, from which the expression of this molecule had been eliminated.

The experimental results indicated that PD-L1-deficient tumour cells inefficiently colonized the spleen and liver of the animals.

They demonstrated that natural killer cells did not depend on PD-1 for their function and were able to eliminate tumour cells with similar efficiency, regardless of PD-L1 expression, while PD-L1 expression in A20 tumour cells protected the tumour from rejection by CD8 T cells.

They confirmed the role of the co-inhibitory ligand PD-L1 as a modulator of the immune response mediated by cytotoxic T cells, while blocking this interaction would not affect the functional activity of natural killer cells.

“PD-L1 expression in leukaemia tumour cells modulates CD8 T cell-mediated responses to tumour-specific antigens, but does not contribute to inhibiting the response mediated by natural killer cells, which correlates with the inability to detect PD-1 expression in these cells when they are infiltrating tumours,” summarises José Ignacio Rodríguez Barbosa, who maintains that they have collaborated closely with the Institute of Biomedicine of Seville and the University of Fribourg, in Switzerland.

Source: University of Leon

Article: https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2022.887348/full