This model provides the advantage of slower tumor growth, allowing for prolonged immunotherapy treatment as well as a much more complete microenvironment than the one developing with injected tumor cells. They are engineered to express an oncogene or to lose a tumor suppressor gene, which favors tumor development, possibly in a tissue-specific fashion. Genetically engineered mouse models (GEMMs) have been developed and used in cancer research. Altogether, due to the low translational potential of such preclinical models ( 1), they were used with caution ( 5). Most importantly, there are inconsistencies between murine and human immune systems both innate and adaptive at different levels including cell composition, protein expression, pathway components and genomic responses ( 3, 4). In addition, tumors tend to grow fast in these models, offering limited time for immune response to fully develop ( 1). Thus, syngeneic murine cancer cells, which are genetically identical cells cultured in vitro and engrafted on murine hosts, have been used although their available repertoire is limited ( 1) and the model lacks cell heterogeneity that characterizes cancer ( 1, 2). Nevertheless, these tumors had the advantage to grow in a physiologically pertinent tumor microenvironment (TME). However, mostly various murine tumors have been used either xenografted or induced by diverse carcinogens, often on a transgenic background. Immunocompetent mouse models have been used for decades in cancer research for their ability to generate antitumor-specific immune responses. Interest in immunotherapy, particularly in immune checkpoint inhibitors (ICIs), has grown over the past decades but their development is slowed down by the lack of adequate pre-clinical animal models allowing valid evaluation of immunotherapies and their combinations. We also highlight the lack of preclinical studies using this model for radiotherapy-based research and argue that it can be a great asset to understand and answer many open questions around radiation therapy such as its presumed associated “abscopal effect”. In this review, we describe, summarize, and discuss the recent advances of humanized mouse models used for cancer immunotherapy research and the challenges faced during their establishment. Humanized mice that can bear both human immune system and human tumors, are increasingly used in recent preclinical immunotherapy studies and represent a remarkably unprecedented tool in this field. Thus, the need for preclinical models that rapidly and safely allow for a better understanding of underlying mechanisms, drug kinetics and toxicity leading to the selection of the best regimen to be translated into the clinic, is of high importance. Clinical trials for novel immunotherapies or unexplored combination regimens either need years of development or are simply impossible to perform like is the case in cancer patients with limited life expectancy. Immunotherapy with checkpoint inhibitors opened new horizons in cancer treatment. 4Department of Medical Oncology, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium.3Laboratory of Cellular Therapy (UTCH), Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium.2Laboratory of Clinical and Experimental Oncology (LOCE), Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium.1Department of Radiation Oncology, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium.Ghanem 2 Philippe Martinive 1 Ahmad Awada 2,4 Dirk Van Gestel 1 Mohammad Krayem 1,2*
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