The research of the University of Milan has been published in “Nature Genetics”
Non-coding RNA molecules deriving from repeated DNA, considered unimportant until a few years ago, are instead fundamental for the activation and functionality of immune cells, in particular of T lymphocytes, and can become a pharmacological target in innovative immunotherapy strategies.
The study, published in Nature Genetics, was coordinated by Beatrice Bodega, professor of Molecular Biology, and Sergio Abrignani, professor of General Pathology, both of the University of Milan and of the National Institute of Molecular Genetics “Romeo and Enrica Invernizzi”, and was created in collaboration with the IRCCS Istituto Clinico Humanitas and the Humanitas University of Milan, the spin-off CheckmAb of the State of Milan, the Great Metropolitan Niguarda Hospital of Milan, the Policlinico of Milan, the San Giuseppe MultiMedica IRCCS hospital of Milan. Research has shown that non-coding RNA molecules, until recently considered worthless, they are essential for the activation and function of immune cells, especially CD4 + T lymphocytes. These RNAs derive from highly repeated sequences in our DNA (the LINE1 sequences) that have colonized the human genome, contributing to its evolution.
The study was conducted on cells deriving from healthy donors and on tumor tissues isolated from neoplastic patients
In particular, the study shows that LINE1 RNAs accumulate in “Naive” type CD4 + T lymphocytes (cells considered immature) and, when these cells are activated, LINE1 RNA molecules decrease drastically. This depends on a different modulation of these molecules in the immature cell and in the differentiated cell, which occurs through a mechanism called splicing of the RNA molecules. The study was conducted on cells deriving from healthy donors and on tumor tissues isolated from neoplastic patients. It is known that lymphocytes present in tumors are no longer able to take action to eliminate cancer cells. Surprisingly, however, tumor-infiltrating CD4 + lymphocytes re-accumulate LINE1 RNAs and researchers have also shown in the laboratory that by silencing these RNAs, intratumoral T lymphocytes regain the ability to eliminate neoplastic cells.
“We believe we have identified a potential new therapeutic target to combine with today’s immunotherapies with antibodies against “Checkpoint inhibitor”, explain Beatrice Bodega and Sergio Abrignani. “The future goal is to create a startup that can develop new therapies that, by turning off LINE1 RNA in intratumoral T lymphocytes, can awaken the silent immune system in the intratumoral microenvironment, so that T lymphocytes can again recognize and destroy neoplastic cells “. The research was conducted thanks to funding from the Regional Foundation for Biomedical Research (FRRB), the Cariplo Foundation and AIRC – the Italian Association for Cancer Research.