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Spontaneous Post-Transplant Disorders in NOD.Cg- Prkdcscid Il2rgtm1Sug/JicTac (NOG) Mice Engrafted with Patient-Derived Metastatic Melanomas.

Radaelli E, Hermans E, Omodho L, Francis A, Vander Borght S, Marine JC, van den Oord J, Amant F - PLoS ONE (2015)

Bottom Line: 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).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.

View Article: PubMed Central - PubMed

Affiliation: VIB11 Center for the Biology of Disease, KU Leuven Center for Human Genetics, Leuven, Belgium; InfraMouse, KU Leuven-VIB, Leuven, Belgium.

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.

No MeSH data available.


Related in: MedlinePlus

Metastatic melanoma xenografts in NOG mice affected by xenogeneic GVHD are effaced by plasma cell-rich lymphoid infiltrates.(A) Xenotransplanted metastatic melanoma is replaced by dense lymphoid infiltrates diffusely expressing human-specific MHC class I molecule HLA-A. HLA-A immunohistochemistry, scale bar = 100 μm. (B and C) Few residual groups of tyrosinase-positive melanoma cells are still detectable among the lymphoid infiltrates. Tyrosinase immunohistochemical staining, scale bar = 200 μm in B and 50 μm in C. Lymphoid infiltrates at the site of transplantation are primarily composed of MUM1p-positive plasma cells (D), CD20-positive mature B cells (E) and CD3-positive T cells. MUM1p, CD20 and CD3 immunohistochemistry, scale bar = 100 μm.
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pone.0124974.g003: Metastatic melanoma xenografts in NOG mice affected by xenogeneic GVHD are effaced by plasma cell-rich lymphoid infiltrates.(A) Xenotransplanted metastatic melanoma is replaced by dense lymphoid infiltrates diffusely expressing human-specific MHC class I molecule HLA-A. HLA-A immunohistochemistry, scale bar = 100 μm. (B and C) Few residual groups of tyrosinase-positive melanoma cells are still detectable among the lymphoid infiltrates. Tyrosinase immunohistochemical staining, scale bar = 200 μm in B and 50 μm in C. Lymphoid infiltrates at the site of transplantation are primarily composed of MUM1p-positive plasma cells (D), CD20-positive mature B cells (E) and CD3-positive T cells. MUM1p, CD20 and CD3 immunohistochemistry, scale bar = 100 μm.

Mentions: In 8 out of 14 mice affected by xenogeneic GVHD-like condition, microscopic changes at site of transplantation were characterized by dense plasma cell-rich lymphoid infiltrates of human origin with severe effacement of melanoma xenografts as demonstrated by the identification of scattered groups of Melan A, HMB45 and/or Tyrosinase-positive tumor cells interspersed among the reactive infiltrates (Fig 3). As observed also in other organs/tissues, plasma cell-rich infiltrates at site of transplantation were composed primarily of CD20/PAX5/BLIMP1-positive mature B cells, BLIMP1/CD138/MUM1p-positive plasma cells and CD3-positive T cells (Fig 3). Similar tumor-effacing plasma cell-rich lymphoid infiltrates were not identified in any of the original metastatic melanoma biopsies considered in this study.


Spontaneous Post-Transplant Disorders in NOD.Cg- Prkdcscid Il2rgtm1Sug/JicTac (NOG) Mice Engrafted with Patient-Derived Metastatic Melanomas.

Radaelli E, Hermans E, Omodho L, Francis A, Vander Borght S, Marine JC, van den Oord J, Amant F - PLoS ONE (2015)

Metastatic melanoma xenografts in NOG mice affected by xenogeneic GVHD are effaced by plasma cell-rich lymphoid infiltrates.(A) Xenotransplanted metastatic melanoma is replaced by dense lymphoid infiltrates diffusely expressing human-specific MHC class I molecule HLA-A. HLA-A immunohistochemistry, scale bar = 100 μm. (B and C) Few residual groups of tyrosinase-positive melanoma cells are still detectable among the lymphoid infiltrates. Tyrosinase immunohistochemical staining, scale bar = 200 μm in B and 50 μm in C. Lymphoid infiltrates at the site of transplantation are primarily composed of MUM1p-positive plasma cells (D), CD20-positive mature B cells (E) and CD3-positive T cells. MUM1p, CD20 and CD3 immunohistochemistry, scale bar = 100 μm.
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getmorefigures.php?uid=PMC4440639&req=5

pone.0124974.g003: Metastatic melanoma xenografts in NOG mice affected by xenogeneic GVHD are effaced by plasma cell-rich lymphoid infiltrates.(A) Xenotransplanted metastatic melanoma is replaced by dense lymphoid infiltrates diffusely expressing human-specific MHC class I molecule HLA-A. HLA-A immunohistochemistry, scale bar = 100 μm. (B and C) Few residual groups of tyrosinase-positive melanoma cells are still detectable among the lymphoid infiltrates. Tyrosinase immunohistochemical staining, scale bar = 200 μm in B and 50 μm in C. Lymphoid infiltrates at the site of transplantation are primarily composed of MUM1p-positive plasma cells (D), CD20-positive mature B cells (E) and CD3-positive T cells. MUM1p, CD20 and CD3 immunohistochemistry, scale bar = 100 μm.
Mentions: In 8 out of 14 mice affected by xenogeneic GVHD-like condition, microscopic changes at site of transplantation were characterized by dense plasma cell-rich lymphoid infiltrates of human origin with severe effacement of melanoma xenografts as demonstrated by the identification of scattered groups of Melan A, HMB45 and/or Tyrosinase-positive tumor cells interspersed among the reactive infiltrates (Fig 3). As observed also in other organs/tissues, plasma cell-rich infiltrates at site of transplantation were composed primarily of CD20/PAX5/BLIMP1-positive mature B cells, BLIMP1/CD138/MUM1p-positive plasma cells and CD3-positive T cells (Fig 3). Similar tumor-effacing plasma cell-rich lymphoid infiltrates were not identified in any of the original metastatic melanoma biopsies considered in this study.

Bottom Line: 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).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.

View Article: PubMed Central - PubMed

Affiliation: VIB11 Center for the Biology of Disease, KU Leuven Center for Human Genetics, Leuven, Belgium; InfraMouse, KU Leuven-VIB, Leuven, Belgium.

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.

No MeSH data available.


Related in: MedlinePlus