Franzese Ornella, Torino Francesco, Fuggetta Maria Pia, Aquino Angelo, Roselli Mario, Bonmassar Enzo, Giuliani Anna, D'Atri Stefania
Department of Systems Medicine, School of Medicine, University of Rome Tor Vergata, Rome, Italy.
Department of Systems Medicine, Medical Oncology, University of Rome Tor Vergata, Rome, Italy.
Oncotarget. 2017 Jun 20;8(25):41641-41669. doi: 10.18632/oncotarget.16335.
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.
40多年前，我们发现用达卡巴嗪治疗小鼠白血病可在体内或体外诱导产生新的移植抗原。数年后，蒂埃里·布恩用一种诱变/致癌化合物（即N-甲基-N'-硝基-N-亚硝基胍）重现了我们称之为“化学异种源化”（CX）、最近又称为“药物诱导异种源化”（DIX）的这一现象。在这两种情况下，DIX的分子基础都依赖于DNA鸟嘌呤的氧-6位甲基加合物诱导的诱变作用。在本综述中，我们阐述了临床使用的三氮烯化合物（即达卡巴嗪和替莫唑胺）与DIX相关的主要免疫药效学特性。近年来，随着免疫检查点抑制剂（ICpI）的发现，肿瘤免疫疗法重回舞台，这些抑制剂显示出非凡的免疫增强活性。在此，我们阐述了一些最有趣的ICpI的显著生化特征及其临床应用的最新状况。此外，我们还阐述了表明体细胞突变负担与癌细胞对宿主免疫反应易感性之间直接关系的文献。当发现DIX时，我们无法令人满意地利用恶性细胞中可能存在的三氮烯诱导的新抗原，因为在临床环境中没有可用的设备来充分增强宿主的免疫反应。如今，ICpI在生存时间方面显示出前所未有的疗效，尤其是当癌细胞伴有高突变负荷时。因此，未来通过适当的药物干预获得的依赖于突变的新抗原似乎揭示了一种提高ICpI对癌症患者治疗效果的新方法。
