title: Spontaneous Post-Transplant Disorders in NOD.Cg- Prkdcscid Il2rgtm1Sug/JicTac (NOG) Mice Engrafted with Patient-Derived Metastatic Melanomas.
abstract: Patient-derived tumor xenograft (PDTX) approach is nowadays considered a reliable preclinical model to study in vivo cancer biology and therapeutic response. NOD scid and Il2rg-deficient mice represent the "gold standard" host for the generation of PDTXs. Compared to other immunocompromised murine lines, these mice offers several advantages including higher engraftment rate, longer lifespan and improved morphological and molecular preservation of patient-derived neoplasms. Here we describe a spectrum of previously uncharacterized post-transplant disorders affecting 14/116 (12%) NOD.Cg- Prkdcscid Il2rgtm1Sug/JicTac (NOG) mice subcutaneously engrafted with patient-derived metastatic melanomas. Affected mice exhibited extensive scaling/crusting dermatitis (13/14) associated with emaciation (13/14) and poor/unsuccessful tumor engraftment (14/14). In this context, the following pathological conditions have been recognized and characterized in details: (i) immunoinflammatory disorders with features of graft versus host disease (14/14); (ii) reactive lymphoid infiltrates effacing xenografted tumors (8/14); (iii) post-transplant B cell lymphomas associated with Epstein-Barr virus reactivation (2/14). We demonstrate that all these entities are driven by co-transplanted human immune cells populating patient-derived tumor samples. Since the exploding interest in the utilization of NOD scid and Il2rg-deficient mice for the establishment of PDTX platforms, it is of uppermost importance to raise the awareness of the limitations associated with this model. The disorders here described adversely impact tumor engraftment rate and animal lifespan, potentially representing a major confounding factor in the context of efficacy and personalized therapy studies. The occurrence of these conditions in the NOG model reflects the ability of this mouse line to promote efficient engraftment of human immune cells. Co-transplanted human lymphoid cells have indeed the potential to colonize the recipient mouse initiating the post-transplant conditions here reported. On the other hand, the evidence of an immune response of human origin against the xenotransplanted melanoma opens intriguing perspectives for the establishment of suitable preclinical models of anti-melanoma immunotherapy.
authors.affiliation: VIB11 Center for the Biology of Disease, KU Leuven Center for Human Genetics, Leuven, Belgium; InfraMouse, KU Leuven-VIB, Leuven, Belgium.
authors.forename: Enrico
authors.initials: E
authors.lastname: Radaelli
authors.affiliation: Gynaecological Oncology, UZ Leuven-Department of Oncology, KU Leuven, Leuven, Belgium.
authors.forename: Els
authors.initials: E
authors.lastname: Hermans
authors.affiliation: VIB11 Center for the Biology of Disease, KU Leuven Center for Human Genetics, Leuven, Belgium.
authors.forename: Lorna
authors.initials: L
authors.lastname: Omodho
authors.affiliation: VIB11 Center for the Biology of Disease, KU Leuven Center for Human Genetics, Leuven, Belgium; InfraMouse, KU Leuven-VIB, Leuven, Belgium.
authors.forename: Annick
authors.initials: A
authors.lastname: Francis
authors.affiliation: Department of Pathology, Laboratory of Morphology and Molecular Pathology, University Hospitals of Leuven, Leuven, Belgium.
authors.forename: Sara
authors.initials: S
authors.lastname: Vander Borght
authors.affiliation: Laboratory for Molecular Cancer Biology, VIB11 Center for the Biology of Disease, KU Leuven Center for Human Genetics, Leuven, Belgium.
authors.forename: Jean-Christophe
authors.initials: JC
authors.lastname: Marine
authors.affiliation: Translational Cell and Tissue Research, Department of Imaging and Pathology, KU Leuven, Leuven, Belgium.
authors.forename: Joost
authors.initials: J
authors.lastname: van den Oord
authors.affiliation: Gynaecological Oncology, UZ Leuven-Department of Oncology, KU Leuven, Leuven, Belgium.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Amant
mesh_terms: D000818:Animals; D001706:Biopsy; D004195:Disease Models, Animal; D005260:Female; D006086:Graft vs Host Disease / Q000209:etiology*; D064593:Heterografts; D006801:Humans; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology / Q000473:pathology; D008297:Male; D008545:Melanoma / Q000276:immunology / Q000473:pathology*; D051379:Mice; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D016513:Mice, SCID; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation / Q000009:adverse effects