SIENA. Why can two patients with the same tumor, treated with the same therapy, have different results? This is the question that has guided research on metastatic melanoma for years, where immunotherapy has changed the treatment outlook but unfortunately does not work for everyone. A new study by researchers at Fondazione Nibit, published in the journal “Science Advances,” now offers a concrete answer: it has identified the biological mechanism by which some tumor cells evade the immune system and a protein that could become the ideal target to stop them.
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The new study
«Immunotherapy has profoundly changed the treatment of metastatic melanoma, but not all patients achieve a lasting benefit. Understanding how resistance to treatment arises and is maintained is essential to develop new therapeutic combinations capable of increasing the number of people who can benefit from these treatments,» explains Michele Maio, full professor of Medical Oncology at the University of Siena, director of the Immuno-Oncology Center of the Azienda ospedaliero-universitaria Senese and president of Fondazione Nibit. The starting point was the Nibit-M4 clinical study, developed by Fondazione Nibit, coordinated by Anna Maria Di Giacomo, full professor of Medical Oncology at the University of Siena, and also supported by Fondazione Airc.
Resistant cells
The trial tested on 19 patients the sequential combination of an epigenetic drug (guadecitabine) and an immunotherapeutic (ipilimumab): the goal was first to “awaken” the tumor making it recognizable, and then attack it with the patient’s activated immune defenses. The long-term results were encouraging but it remained to be understood why the strategy worked only on some of them. To find out, the researchers analyzed, in collaboration with the Center of professor Michele Ceccarelli, full professor of Computational Biology at the University of Miami in Florida, the biopsies of patients before and during treatment at the single-cell level: in patients who did not respond to therapy, melanoma cells changed identity, regressing to an immature and very plastic state just to survive the immune attack; these resistant cells were clustered in compact areas at the center of the tumor mass, and this geometric structure stabilized their behavior, protecting each other; the combined analysis of gene and epigenetic profiles identified the NFATC2 protein as the “director” that keeps melanoma cells locked in this immature and treatment-refractory state.
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The importance of the study
The epigenetic drug reactivates parts of the DNA normally silent, generating an alarm signal that calls the immune system. However, the NFATC2 protein orchestrates a particularly resistant cellular state. The results were also confirmed on a much larger sample of over 400 patients, from eight independent studies: those showing the presence of these immature cells after treatment had a worse prognosis. «This research allows us to take an important step forward,» concludes Maio. «We no longer just observe whether a therapy works, but we understand how it modifies the tumor and why some cells resist. The future goal is to develop strategies capable both of activating the immune system and preventing melanoma from adapting and hiding. This is the direction we are already working on with the new Nibit-Ml1 clinical study.»
