Humanized NOD-SCID IL2rg–/– mice as a preclinical model for cancer research and its potential use for individualized cancer therapies

doi:10.1016/j.canlet.2013.10.015

Cancer Letters

Volume 344, Issue 1, 1 March 2014, Pages 13-19

https://doi.org/10.1016/j.canlet.2013.10.015 Get rights and content

Highlights

•
We summarize the characteristics and the development of humanized NOD-SCID-IL2rg^–/– mice.
•
We compare the human tumor xenograft models between NOD-SCID-IL2rg^–/– mice and other immunodeficient mice respectively.
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We conclude studies using NOD-SCID-IL2rg^–/– mice on individualized cancer therapy.
•
We discuss limitations of NOD-SCID-IL2rg^–/– mice xenograft models for cancer study.

Abstract

Humanized mouse models have been developed and utilized in cancer research for decades. Newly developed combined immunodeficient NOD-SCID-IL2rg^–/– mice are more permissive for human cells and tissue engraftment. In this review, we discuss the use of NOD-SCID-IL2rg^–/– mice as a preclinical tool in cancer research and its potential use for individualized cancer therapies.

Introduction

For more than half a century, substantial progress has been made in developing therapies for human cancers due to the contribution of clinically relevant animal models. However, translation of the discoveries from mouse models to clinical trials has been hampered by the genetic differences between human and inbred mouse strains. Implantation of human cells and tissues into laboratory mouse, i.e., xenograft implantation, will induce rejection of human tissues by host mouse with intact immune system. From the first athymic mouse model [1] for cancer research to the latest genetically modified, highly immunodeficient mouse strains, xenografting in humanized mouse model has been a valuable tool to improve treatments against human cancers.

Since the improvement of engraftment of human peripheral blood mononuclear cells (PBMCs) and hematopoietic stem cells (HSCs) in severe combined immunodeficiency (SCID) mice [2], [3], significant advance has been made in the areas of human hematopoiesis, infectious disease, autoimmunity and tumor immunology in the last three decades. However, the residual adaptive and innate immunity in host mice remain a limiting factor affecting establishment of human tumor xenograft. Although NOD-SCID mice are more efficient for human PBMCs and HSCs engraftment [4], [5], residual innate immune activities including NK cells and short life span limit human cell and tissue engraftment [6]. Further efforts had been made to promote the xenograft efficiency by introducing other genetic deficiencies for certain molecules into NOD-SCID strain. Recently, targeted mutations at interleukin-2 receptor (IL-2R) γ chain locus (IL2rg; or γc) [7], [8], which results in complete absence of NK cells [9], [10], greatly improved engraftment of human cells and tissues. There are several distinct strains of IL2rg^–/– mice with regard to their parental immunodeficiency combinations [7], [8], [11], [12]. Among these strains the NOD-SCID IL2rg^–/– mice are currently characterized as the most humanized by inducing IL2rg^–/– mutation into NOD-SCID strain, compared with any previous immunodeficient humanized mice [7], [8] (Table 1). Here we summarize and discuss the use of NOD-SCID IL2rg^–/– mice as a preclinical tool in cancer research and its potential use for individualized cancer therapies.

Section snippets

Development of humanized NOD-SCID IL2rg^–/– mice

Progress of developing humanized mice depends on the advances in genetic modifications on immunodeficient mice. SCID mouse was the first major breakthrough in humanized mice which allowed human cells and tissues to engraft in these mice in 1988 [2], however, engraftment efficiency is low due to the lack of an intact, completely developed immune system. Since the development of NOD-SCID in 1995, this breakthrough remarkably improved the engraftment of human cells and tissues into a mouse strain.

Characteristics of NOD-SCID IL2rg^–/– mice

The NOD-SCID IL2rg^–/– mice were established by an 8–10th generation backcrossing of IL2rg^–/– mice to NOD-SCID mice. The degree of immunodeficiency of NOD-SCID IL2rg^–/– mice is determined and thereafter enhanced from the immune defects of their parental strains. SCID mutation gives rise to immunodeficient mice that lack functional T cells and B cells [14]. NOD inbred strain has reduced innate immunity as measured by macrophage and NK cell dysfunction and complement-dependent hemolytic activity

Cancer biology study based on humanized NOD-SCID IL2rg^–/– mice model

Since the development of nude mice, immunodeficient mice have been used to study human tumor biology, angiogenesis and metastasis. However, innate immunity of the mice, especially the NK cells can impede tumor growth and metastasis. Most immunocompromised mice such as nude mice (compensatory increased NK cell activity and tumoricidal macrophage), SCID-beige (delayed NK cell activation, but not loss [27]), or even in NOD-SCID (low NK cell activity), have not provided a suitable microenvironment

Potential use in individualized cancer therapy

The treatment of cancer has been impeded not only by the lack of relevant tumor models for clinical use, but the heterogeneity of cancer patients. Current screening models for anti-tumor drug efficacy generally use tumor cell lines by which recapitulation of tumor features cannot be realized due to the derivation of in vitro cultivated tumor cell line and a lack of tumor stromal cells [45]. Therefore, value of those models to predict the patients’ response to anti-cancer treatment is limited.

Limitation and development of NOD-SCID IL2rg^–/– mice

Despite the advantages of using NOD-SCID-IL2rg^–/– mice, there are still limitations when using these mice in human cancer research. Primarily there are still innate immune cells present such as macrophages, DCs and neutrophils that influence engraftment efficacy. To eliminate these cells by transgenic or RNAi techniques might result in higher engraftment rate [65], [66]. The nature of NOD-SCID-IL2rg^–/– mice cannot provide species-specific growth factors for the development of human cells.

Conclusion

The development of fully humanized mice becomes more relevant as a preclinical tool in translational biomedical research given the shortcomings of the use of immunocompetent mice and tumor cell lines in cancer research. Recently developed NOD-SCID IL2rg^–/– mice based on SCID mutation and IL2rg^–/– gene has overcome many weak points of previous mice models, and shows high capacity for human cells/tissues engraftment. NOD-SCID IL2rg^–/– mice should be utilized to expand the study of carcinogenesis

Conflict of Interest

None.

Acknowledgments

Dr. Qianjun Zhou thank Dr. Richard B. Bankert and Dr. Raymond J. Kelleher Jr. for their meticulous instructions during the postdoc research in their lab.

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Mini-reviewHumanized NOD-SCID IL2rg–/– mice as a preclinical model for cancer research and its potential use for individualized cancer therapies

Highlights

Abstract

Introduction

Section snippets

Development of humanized NOD-SCID IL2rg–/– mice

Characteristics of NOD-SCID IL2rg–/– mice

Cancer biology study based on humanized NOD-SCID IL2rg–/– mice model

Potential use in individualized cancer therapy

Limitation and development of NOD-SCID IL2rg–/– mice

Conclusion

Conflict of Interest

Acknowledgments

Blood

Blood

Immunity

Blood

Blood

Blood

Biochem. Biophys. Res. Commun.

Eur. J. Cancer

Eur. J. Cancer

Biochem. Biophys. Res. Commun.

Blood

Heterotransplantation of a human malignant tumour to “Nude” mice

Acta Pathologica et Microbiologica Scandinavica

Transfer of a functional human immune system to mice with severe combined immunodeficiency

Nature

Cytokine stimulation of multilineage hematopoiesis from immature human cells engrafted in SCID mice

Science

High levels of human peripheral blood mononuclear cell engraftment and enhanced susceptibility to human immunodeficiency virus type 1 infection in NOD/LtSz-scid/scid mice

J. Infect. Dis.

Multiple defects in innate and adaptive immunologic function in NOD/LtSz-scid mice

J. Immunol.

Human lymphoid and myeloid cell development in NOD/LtSz-scid IL2R gamma null mice engrafted with mobilized human hemopoietic stem cells

J. Immunol.

Development of a human adaptive immune system in cord blood cell-transplanted mice

Science

Lymphoid development in mice with a targeted deletion of the interleukin 2 receptor gamma chain

Proc. Natl. Acad. Sci. USA

DNA-dependent kinase (p350) as a candidate gene for the murine SCID defect

Science

Efficient xenoengraftment in severe immunodeficient NOD/Shi-scid IL2rgammanull mice is attributed to a lack of CD11c+B220+CD122+ cells

J. Immunol.

Humanized mice in translational biomedical research

Nat. Rev. Immunol.

Transgenic expression of human signal regulatory protein alpha in Rag2–/–gamma(c)–/– mice improves engraftment of human hematopoietic cells in humanized mice

Proc. Natl. Acad. Sci. USA

Immunodeficient mouse strains display marked variability in growth of human melanoma lung metastases

Clin. Cancer Res.

Human acute leukemia cells injected in NOD/LtSz-scid/IL-2Rgamma null mice generate a faster and more efficient disease compared to other NOD/scid-related strains

Int. J. Cancer. J. Int. du Cancer

Enhanced human CD4+ T cell engraftment in beta2-microglobulin-deficient NOD-scid mice

J. Immunol.

Reconstitution of huPBL-NSG mice with donor-matched dendritic cells enables antigen-specific T-cell activation

J. Neuroimmune Pharmacol.

Establishment of a rhabdomyosarcoma xenograft model in human-adapted mice

Oncol. Rep.

NOD/LtSz-Rag1nullPfpnull mice: a new model system with increased levels of human peripheral leukocyte and hematopoietic stem-cell engraftment

Transplantation

Humanized mouse model of ovarian cancer recapitulates patient solid tumor progression, ascites formation, and metastasis

PloS one

NOD-scid IL2R gammanull mice engrafted with human peripheral blood mononuclear cells as a model to test therapeutics targeting human signaling pathways

J. Trans. Med.

Role of NK cells in tumour growth and metastasis in beige mice

Nature

Efficient tumour formation by single human melanoma cells

Nature

Identification of a key molecular regulator of liver metastasis in human pancreatic carcinoma using a novel quantitative model of metastasis in NOD/SCID/gammacnull (NOG) mice

Int. J. Oncol.

Long-term engraftment and expansion of tumor-derived memory T cells following the implantation of non-disrupted pieces of human lung tumor into NOD-scid IL2Rgamma(null) mice

J. Immunol.

Mini-review
Humanized NOD-SCID IL2rg^–/– mice as a preclinical model for cancer research and its potential use for individualized cancer therapies

Development of humanized NOD-SCID IL2rg^–/– mice

Characteristics of NOD-SCID IL2rg^–/– mice

Cancer biology study based on humanized NOD-SCID IL2rg^–/– mice model

Limitation and development of NOD-SCID IL2rg^–/– mice