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.
Highlights
Patient-derived tumor xenograft (PDTX) approach is nowadays considered one of the most accurate preclinical tools to study in vivo biology and therapeutic response of individual human cancers [1,2]
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
A revolutionary aspect of NSG and NOG mice is the ability to promote efficient engraftment and expansion of diverse repertoires of leukocytes from different animal species including humans [11,23]. Thanks to this unique feature, both mouse lines are currently widely exploited in the preclinical field to generate mouse models with humanized immune system for studying immunopathological conditions [e.g. GVHD, delayed-type hypersensitivity (DTH)] [24,25], viral infections primarily targeting immune cells [e.g. human immunodeficiency virus (HIV) and Epstein-Barr Virus (EBV) infections] [26]) and immunotherapeutic strategies [27,28]
Summary
Patient-derived tumor xenograft (PDTX) approach is nowadays considered one of the most accurate preclinical tools to study in vivo biology and therapeutic response of individual human cancers [1,2]. A variety of PDTX models have been successfully established for preclinical/clinical drug testing and biomarker identification in diverse human neoplasms including ovarian, pancreatic, breast, skin and prostate cancers [2,3,4,5,6,7]. In this context, PDTX approach has been shown to be biologically stable and accurately reflect the original patient tumor with regards to expression profile, mutational spectrum and molecular signaling [4,5,8]. The targeted mutation in the γ chain of the IL-2 receptor leads to deficiencies in cytokine signaling and failure of clonal lymphocyte expansion [9,10,11,12,13,14]
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