A group of researchers at San Raffaele Hospital and Vita-Salute San Raffaele University, headed by Chiara Bonini, full professor of Applied Medical Technical Sciences at UniSR Faculty of Medicine and Surgery, has demonstrated that studying tumor microenvironment in colorectal tumors and related hepatic metastasis might open new paths for the development of innovative immunotherapies aimed at treating these tumors. The study, published on the prestigious scientific journal Gut, is part of a program granted by AIRC 5x1000, that aims to generate innovative therapies for treatment of liver metastasis deriving from colorectal and pancreatic tumor.

The research project

Among the immune cells that infiltrate the tumor tissue in patient with primitive and metastatic tumor, T lymphocytes are widely spread and represent the first defense mechanism of our organism. Inside the tumor tissue, however, multiple factors prevent their correct functionality.

More precisely, through precise analysis aimed to identify the T-cells phenotype infiltrating tumor, it was discovered that the lymphocytes infiltrating the primitive colorectal tumor and the resulting liver metastasis share the same enzyme, defined CD39, that is involved into metabolic processes amd also belongs to a series of molecules that are called “inhibition receptors” because of their ability to prevent the correct functioning of T-cells.

Thanks to CRISPR/Cas9, a technique that operates like “molecular scissors”, researchers have eliminated CD39 from T-cells. They also have replaced the receptor naturally present on the T-cell surface (TCR, T Cell Receptor) with a specific-tumor receptor, isolated from blood cells of healthy donors, capable of recognizing HER-2 protein, already a target of some antitumor therapies currently used in clinical practice.

These genetic modifications of lymphocytes have allowed to obtain lots of T-Cells directed against tumor and capable to resist to inhibitory signals deriving from tumor microenvironment.

“At the basis of this research there is in-depth characterization of tumor microenvironment, which proved to be of fundamental importance in choosing the type of genetic manipulation to effectuate on T-cells. This was possible thanks to samples coming from the tumor tissue and the healthy tissue of patients who accepting to participate to this project and generously making themselves available for scientific goals. This opened new important paths and perspectives in the treatment of colorectal tumor” has declared doctor Alessia Potenza, first author of this study.

“The comparative analysis between primary tumor and metastatic sample allowed us to identify common molecular mechanisms that operates in both tissues”, adds dr. Chiara Balestrieri, co-first author of the research. Dr. Eliana Ruggiero, last author of the study, underlines:“the identification of molecular targets paved the way to the validation and development of therapeutic genes aimed at arming immune system cells against this type of tumor”. “Pre-clinical studies aimed at validateing security and efficacy of lymphocytes engineered to recognize colorectal tumor are currently in progress” explains Chiara Bonini, coordinator of the Research Program on metastasis, granted by AIRC in the context of AIRC5x1000 call.