Spontaneous Post-Transplant Disorders in NOD.Cg- <i>Prkdc^scid Il2rg^tm1Sug</i>/JicTac (NOG) Mice Engrafted with Patient-Derived Metastatic Melanomas

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.患者来源的肿瘤异种移植（Patient-derived tumor xenograft, PDTX）模型目前被认为是研究体内癌症生物学与治疗反应的可靠临床前模型。NOD-scid及白细胞介素2受体γ链缺陷（Il2rg-deficient）小鼠是构建PDTX的“金标准”受体动物。相较于其他免疫缺陷小鼠品系，此类小鼠具备诸多优势：肿瘤移植定植率更高、生存期更长，且能更好保留患者来源肿瘤的形态学与分子学特征。本文报道了一系列此前未被表征的移植后并发症，涉及14/116（12%）的NOD.Cg-Prkdcscid Il2rgtm1Sug/JicTac（NOG）小鼠，这些小鼠皮下移植了患者来源的转移性黑色素瘤。患病小鼠表现为广泛脱屑/结痂性皮炎（13/14），伴随消瘦（13/14）以及肿瘤移植定植失败或成功率极低（14/14）。在此背景下，我们详细鉴定并表征了以下病理状态：(i) 具备移植物抗宿主病（graft versus host disease, GvHD）特征的免疫炎症性疾病（14/14）；(ii) 反应性淋巴浸润取代异种移植瘤（8/14）；(iii) 与Epstein-Barr病毒（EB病毒）再激活相关的移植后B细胞淋巴瘤（2/14）。本研究证实，所有上述病变均由共移植的人类免疫细胞驱动，此类细胞定植于患者来源的肿瘤样本中。鉴于当前学界对利用NOD-scid及Il2rg缺陷小鼠构建PDTX平台的兴趣激增，因此亟需提升对该模型相关局限性的认知。本文描述的此类并发症会降低肿瘤移植定植率并缩短动物生存期，在疗效及个体化治疗研究中可能成为主要的混杂因素。NOG模型中此类病变的出现，反映了该小鼠品系能够高效定植人类免疫细胞的特性。共移植的人类淋巴样细胞确实能够定植于受体小鼠体内，从而引发本文报道的移植后病变。另一方面，人类免疫细胞针对异种移植黑色素瘤产生免疫应答的证据，为构建抗黑色素瘤免疫治疗的合适临床前模型开辟了极具吸引力的研究前景。