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.

Tumor characteristics associated with engraftment of patient‐derived non–small cell lung cancer xenografts in immunocompromised mice

“…2,33 The proliferation of EBV-positive B cells in tumor samples also has been reported to result in the formation of human B-cell lymphomas and the failure of PDX growth in specimens from patients with several types of cancer, including lung cancer. 35 In addition to lymphoma, immune cells present within tumor samples and cotransplanted into the subcutis of NSG mice can induce graft-versushost disease before successful primary tumor engraftment, 30 or coexist with tumor cells in early passages of PDXs. 35 In addition to lymphoma, immune cells present within tumor samples and cotransplanted into the subcutis of NSG mice can induce graft-versushost disease before successful primary tumor engraftment, 30 or coexist with tumor cells in early passages of PDXs.…”

Hedgehog pathway activation in T-cell acute lymphoblastic leukemia predicts response to SMO and GLI1 inhibitors

“…Immunoflorescence and/or immunopreoxidase stain were performed on paraffin sections using the following antibodies: CD3e (Santa Cruz), cleaved caspase-3 (Cell Signaling), green fluorescent protein (GFP), Ly75 (Abcam), UEA1 lectin (Vector Laboratories), Ki67 (ThermoScientific), Alexa Fluor 568 donkey antirabbit or Alexa Fluor 488 donkey anti-goat (Molecular Probes), goat anti-rabbit EnVision1/HRP reagent (Dako), and biotinilated rabbit anti-goat (Abcam). The degree of splenic colonization by leukemic cells was determined by staining with human HLA-A (Abcam) as described 33 with a digital image analysis algorithm created on the ImageJ software platform. Proliferation and apoptosis were measured via cleaved caspase-3 and phospho-histone H3 (Cell Signaling).…”

Immune Relevant and Immune Deficient Mice: Options and Opportunities in Translational Research

“…375,400,[537][538][539][540] Biosecurity: contaminated biologicals Rodent pathogens (latent infections): contaminated serum with mousepox. 378,410,434,451,452,541 Human pathogens: contaminated human cell lines (humanized mice and patient derived xenografts mice). Mycoplasma arginini: suppurative arthritis in Prkdc scid mice (contaminated cell lines).…”