title: Tumor immunotherapy: drug-induced neoantigens (xenogenization) and immune checkpoint inhibitors.
abstract: More than 40 years ago, we discovered that novel transplantation antigens can be induced in vivo or in vitro by treating murine leukemia with dacarbazine. Years later, this phenomenon that we called "Chemical Xenogenization" (CX) and more recently, "Drug-Induced Xenogenization" (DIX), was reproduced by Thierry Boon with a mutagenic/carcinogenic compound (i.e. N-methyl-N'-nitro-N-nitrosoguanidine). In both cases, the molecular bases of DIX rely on mutagenesis induced by methyl adducts to oxygen-6 of DNA guanine. In the present review we illustrate the main DIX-related immune-pharmacodynamic properties of triazene compounds of clinical use (i.e. dacarbazine and temozolomide).In recent years, tumor immunotherapy has come back to the stage with the discovery of immune checkpoint inhibitors (ICpI) that show an extraordinary immune-enhancing activity. Here we illustrate the salient biochemical features of some of the most interesting ICpI and the up-to-day status of their clinical use. Moreover, we illustrate the literature showing the direct relationship between somatic mutation burden and susceptibility of cancer cells to host's immune responses.When DIX was discovered, we were not able to satisfactorily exploit the possible presence of triazene-induced neoantigens in malignant cells since no device was available to adequately enhance host's immune responses in clinical settings. Today, ICpI show unprecedented efficacy in terms of survival times, especially when elevated mutation load is associated with cancer cells. Therefore, in the future, mutation-dependent neoantigens obtained by appropriate pharmacological intervention appear to disclose a novel approach for enhancing the therapeutic efficacy of ICpI in cancer patients.
authors.affiliation: Department of Systems Medicine, School of Medicine, University of Rome Tor Vergata, Rome, Italy.
authors.forename: Ornella
authors.initials: O
authors.lastname: Franzese
authors.affiliation: Department of Systems Medicine, Medical Oncology, University of Rome Tor Vergata, Rome, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Torino
authors.affiliation: Institute of Translational Pharmacology, National Council of Research, Rome, Italy.
authors.forename: Maria Pia
authors.initials: MP
authors.lastname: Fuggetta
authors.affiliation: Department of Systems Medicine, School of Medicine, University of Rome Tor Vergata, Rome, Italy.
authors.forename: Angelo
authors.initials: A
authors.lastname: Aquino
authors.affiliation: Department of Systems Medicine, Medical Oncology, University of Rome Tor Vergata, Rome, Italy.
authors.forename: Mario
authors.initials: M
authors.lastname: Roselli
authors.affiliation: Department of Systems Medicine, School of Medicine, University of Rome Tor Vergata, Rome, Italy.|Institute of Translational Pharmacology, National Council of Research, Rome, Italy.
authors.forename: Enzo
authors.initials: E
authors.lastname: Bonmassar
authors.affiliation: Institute of Translational Pharmacology, National Council of Research, Rome, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Giuliani
authors.affiliation: Laboratory of Molecular Oncology, Istituto Dermopatico dell'Immacolata-IRCCS, Rome, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: D'Atri
mesh_terms: D000818:Animals; D004260:DNA Repair; D006801:Humans; D007125:Immunogenetics; D007167:Immunotherapy / Q000379:methods*; D051379:Mice; D058990:Molecular Targeted Therapy / Q000379:methods; D009369:Neoplasms / Q000235:genetics / Q000276:immunology / Q000628:therapy*; D014226:Triazenes / Q000276:immunology / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D014226:Triazenes
keywords: DNA repair; cancer immunotherapy; drug-induced neoantigens; immune checkpoints; triazene compounds