Colorectal cancer: study of the microenvironment opens up new possible immunotherapies

A group of researchers from the IRCCS San Raffaele Hospital and the Vita-Salute San Raffaele University, led by Professor Chiara Bonini, full professor of Hematology at the Faculty of Medicine and Surgery of UniSR, has demonstrated how the study of the tumor microenvironment in colorectal tumors and related liver metastases may open new avenues for the development of innovative immunotherapies for the treatment of these tumors.

The study, published in the prestigious scientific journal Gut, is part of a program funded by AIRC 5x1000, which aims to generate innovative therapies for the treatment of liver metastases resulting from colon and pancreatic tumors.

Among the immune cells that infiltrate the tumor tissue of patients with primary and metastatic colorectal cancer, T lymphocytes are present in greater numbers and represent our body's first defense. Inside the tumor tissue, however, a series of factors prevent their correct functionality.

More precisely, through analyzes aimed at precisely identifying the phenotype of the tumor-infiltrating T lymphocytes, it was discovered that the lymphocytes infiltrating the primary colorectal tumor and the resulting liver metastases have in common an enzyme involved in metabolic processes, the CD39, which is part of a series of molecules called "inhibitory receptors" because they put a brake on the correct functioning of T lymphocytes.

Using CRISPR/Cas9 technology, a complex that acts like "molecular scissors", the researchers eliminated CD39 from T lymphocytes. They also replaced the receptor naturally present on the surface of T lymphocytes (TCR, T Cell Receptor) with a tumor-specific receptor, isolated from the blood cells of healthy donors, capable of recognizing the HER-2 protein, already a target of some anti-tumor therapies used in clinical practice.

These genetic modifications of lymphocytes have made it possible to obtain an "army of lymphocytes" directed against the tumor and capable of resisting the inhibitory signals deriving from the tumor microenvironment.

“The basis of this study is an in-depth characterization of the tumor microenvironment, which proved to be of fundamental importance in choosing the type of genetic manipulation to be carried out on T lymphocytes. This was made possible thanks to the samples coming from the tumor tissue and from the healthy tissue of patients who, by agreeing to participate in this project, have generously made themselves available to scientific research, opening new important perspectives in the treatment of colorectal cancer"

declared Dr. Alessia Potenza, first author of the study.

“The comparative analysis between the primary tumor and the metastatic sample allowed us to identify common molecular mechanisms that act in both tissues”

adds Dr. Chiara Balestrieri, co-first author of the study.

Dr. Eliana Ruggiero, the last author of the work, underlines:

“The identification of target molecules has opened the way to the development and validation of therapeutic genes, aimed at arming the cells of the immune system against this type of tumor.”

“Preclinical studies aimed at validating the safety and efficacy of lymphocytes engineered to recognize colorectal cancer are currently underway at our Institute,” declares Chiara Bonini, coordinator of the Metastasis Research Program funded by AIRC in the context of the AIRC5x1000 call.