The road of immunotherapy to fight breast cancer

Data from a study carried out jointly by researchers from theInstitute for Endocrinology and Experimental Oncology of the National Research Council (CNR-IeoS) and theUniversity of Naples Federico II add an important piece to the understanding of the complex interactions between the immune system and breast cancer, paving the way for the development of new strategies for the prognosis and treatment of this disease.

The group was coordinated by Veronica De Rosa, an immunologist at CNR-IeoS, in collaboration with Francesca di Rella of the Pascale Foundation National Cancer Institute, Antonio Pezone and Irene Cantone, who are afferent, respectively, to the Department of Biology and the Department of Molecular Medicine and Medical Biotechnology at the University of Frederick. The researchers discovered the prognostic role of a particular type of immune system cells in breast cancer, known as regulatory T lymphocytes (Treg for short). These cells are present at high concentrations in both primary tumors and in the blood of women with poorer prognosis, and are also associated with the development of particularly aggressive tumor microenvironments. Under normal conditions, Treg lymphocytes are responsible for controlling the body's immune responses, maintaining their balance; but in these types of cancer they can be an important target of treatment: if selectively eliminated, in fact, breast cancer can be effectively destroyed.

The findings, published in the journal Science Advances, emerged during a study initiated in 2016 thanks to support obtained under the TRIDEO call co-funded by AIRC Foundation for Cancer Research and Fondazione Cariplo. Veronica De Rosa (CNR-Ieos) explains, "Treg lymphocytes play a crucial role in the course of cancer and especially breast cancer. They, in fact, limit the antitumor immune response through the expression of inhibitory surface molecules, known as checkpoints. This basically promotes the progression and subsequent metastasis of the tumor. However, if Treg lymphocytes are blocked, especially in the early stages of the disease, this could allow the immune system to reactivate to destroy the tumor. This is precisely the principle on which immunotherapy is based, which very often has Treg lymphocytes as its therapeutic target."

The development of a strategy based on the elimination of Treg cells in order to induce or boost the anti-tumor immune response is, however, particularly complex. "Numerous ongoing clinical trials pursue this goal. However, Treg lymphocytes are not all the same. It is precisely their heterogeneity that makes it difficult to identify specific markers with which to discriminate Tregs present in the blood, which are important for maintaining proper immune function, from those present within the tumor and allowing it to grow," the researcher adds. "Our research group has shown that primary tumors of women with hormone-positive breast cancer have higher amounts of Treg lymphocytes expressing a variant of the FOXP3 protein (FOXP3E2). By measuring their frequency in the blood using the liquid biopsy technique, we were able to predict the patients' prognosis as early as at the time of diagnosis." The study was made possible thanks to the contributions of Francesca di Rella, oncologist at the National Cancer Institute Fondazione Pascale, and Antonello Accurso, oncology surgeon at the University Federico II: over the past five years, patients with early-stage breast cancer, before they started therapy, were enrolled in the clinical trial at both centers.

In addition, computational analysis of a database known as The Cancer Genome Atlas (TCGA) on about 1,000 patients was conducted by Antonio Pezone, a molecular pathologist, and Irene Cantone, a geneticist. Their analysis confirmed that measuring Treg lymphocytes expressing FOXP3E2 within tumor tissue can anticipate both prognosis and possible relapse by up to 20 years not only in women with breast cancer (of all subtypes), but also in patients with renal papillary carcinoma, squamous cell carcinoma of the cervix, and lung adenocarcinoma.

The results obtained, if confirmed in larger clinical trials, could make it possible to develop new prognostic and predictive markers and to identify highly specific therapeutic targets, with the goal of improving the lives of people with cancer.