[An overview of immune checkpoint inhibitors toxicities]. / Toxicité des immunothérapies anti-cancéreuses.

The development of immune checkpoint inhibitors has led to many breakthroughs in cancer treatment. As their use in many types of cancer expands, oncologists have seen the emergence of a whole new set of adverse events that require specific treatment and attention as they can lead to treatment discontinuation, hospitalization, and death. The molecular pathways targeted by these new pharmaceutical agents aim to remove the inhibition on the anti-tumoral immune response exerted by cancer cells. However, in doing so, they also impact mechanisms important for self-tolerance, and lead to autoimmune-related reactions. Those adverse events can affect every organ, with various frequencies, sometimes a long time after the end of treatment. The following presentation endeavours to list the reported immune adverse events classified by affected organs and gives an overview of the proposed treatment and patient care.

Title: Toxicité des immunothérapies anti-cancéreuses. Abstract: Le développement des inhibiteurs des points de contrôle immunitaires représente aujourd'hui un enjeu majeur en cancérologie en termes de gestion des toxicités induites par ces molécules qui ciblent des mécanismes moléculaires clés de la tolérance immunitaire, que les tumeurs détournent pour échapper à la surveillance immunitaire. Les effets secondaires de ces molécules peuvent affecter, avec des fréquences variées - et parfois très à distance de l'administration - l'ensemble des organes. Dans cette revue, nous présentons les différents effets secondaires de ces traitements et les grands principes de leur prise en charge actuelle.

Fanconi anemia A protein participates in nucleolar homeostasis maintenance and ribosome biogenesis.

Fanconi anemia (FA), the most common inherited bone marrow failure and leukemia predisposition syndrome, is generally attributed to alterations in DNA damage responses due to the loss of function of the DNA repair and replication rescue activities of the FANC pathway. Here, we report that FANCA deficiency, whose inactivation has been identified in two-thirds of FA patients, is associated with nucleolar homeostasis loss, mislocalization of key nucleolar proteins, including nucleolin (NCL) and nucleophosmin 1 (NPM1), as well as alterations in ribosome biogenesis and protein synthesis. FANCA coimmunoprecipitates with NCL and NPM1 in a FANCcore complex-independent manner and, unique among the FANCcore complex proteins, associates with ribosomal subunits, influencing the stoichiometry of the translational machineries. In conclusion, we have identified unexpected nucleolar and translational consequences specifically associated with FANCA deficiency that appears to be involved in both DNA damage and nucleolar stress responses, challenging current hypothesis on FA physiopathology.