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Humanized Mouse Xenograft Models: Narrowing the Tumor–Microenvironment Gap J Published OnlineFirst September 1, 2016; DOI: 10.1158/0008-5472.CAN-16-1260 Cancer Review Research Humanized Mouse Xenograft Models: Narrowing the Tumor–Microenvironment Gap J. Jason Morton1, Gregory Bird2, Yosef Refaeli2,3, and Antonio Jimeno1,3,4 Abstract Cancer research has long been hampered by the limitations patients. This setting also facilitates the examination of inves- of the current model systems. Both cultured cells and mouse tigational cancer therapies, including new immunotherapies. xenografts grow in an environment highly dissimilar to that of This review discusses recent advancements in the generation their originating tumor, frequently resulting in promising treat- and application of HM models, their promise in cancer ments that are ultimately clinically ineffective. The develop- research, and their potential in generating clinically relevant ment of highly immunodeficient mouse strains into which treatments. This review also focuses on current efforts to human immune systems can be engrafted can help bridge this improve HM models by engineering mouse strains expressing gap. Humanized mice (HM) allow researchers to examine human cytokines or HLA proteins and implanting human xenograft growth in the context of a human immune system bone, liver, and thymus tissue to facilitate immune cell and resultant tumor microenvironment, and recent studies maturation and trafficking. Finally, we discuss how these have highlighted the increased similarities in attendant tumor improvements may help direct future HM model cancer structure, metastasis, and signaling to those features in cancer studies. Cancer Res; 1–6. Ó2016 AACR. Introduction an immune response against implanted tissues. NOD mice lack innate immunity. The subsequently identified SCID mice lack Humanized mice: innovative research tools both T and B cells and can be successfully engrafted not only with A barrier to the adequate study of human disease is the human tissues but also with hematopoietic cells. Their utility is availability of suitable animal models. Many model systems either somewhat limited by the presence of natural killer (NK) cells and cannot propagate the disease in question or provide a foreign by leaky expression of T and B cells as the mouse ages. This milieu, not representative of the conditions in humans (1). To leakiness has been eliminated in the RAG-1 and RAG-2 mice, address these challenges, chimeric systems designed to incorpo- À À although NK cells remain. The NSG (NOD/SCID-IL2g / ) strain, rate relevant human genes or tissues into a disease model organ- produced by the targeted mutation of the IL2 receptor g-chain ism have been developed. Genetically modified yeast, flies, and locus in a previously bred NOD/SCID strain, lacks T cells, B cells, mice have greatly facilitated medical research. More recently, the macrophages, NK, and NKT cells and has become an increasingly human immune system has been partially reconstituted in mice. used platform for HM development (6). These "humanized mice" (HM) aim at harboring an immune In this review, we will address the state of the art of the environment capable of more accurately reflecting that present in development and utilization of HM for cancer research, with human diseases (2). HM variations have proven key in the study of a particular focus on the challenges facing HM and their allograft rejection and autoimmune diseases, as well as in research implementation. investigating transmissible diseases, such as the human immu- nodeficiency virus and viral hepatitis, among others (3, 4). HM models have become feasible as a result of the identifica- State of the Art in Cancer Research tion of increasingly immunocompromised strains of mice into The complexity of the cancer microenvironment which a human immune system could be successfully engrafted The uncontrolled cell division emblematic of cancer is highly (5). Athymic nude mice lack T cells, so are incapable of mounting adaptive to the selective conditions imposed by the surrounding immune microenvironment (7). Tumor cells lines quickly evolve to the conditions present in a tissue culture environment. Even 1Division of Medical Oncology, Department of Medicine, University of when patient tumor tissue is implanted directly into traditional 2 Colorado School of Medicine, Aurora, Colorado. Department of Der- xenograft mouse models, the immunodepleted murine environ- matology, University of Colorado School of Medicine, Aurora, Color- ado. 3Charles C. Gates Center for Regenerative Medicine and Stem Cell ment often produces different experimental outcomes to treat- Biology, University of Colorado School of Medicine, Aurora, Colorado. ment than those seen in the patient (8). The interplay between the 4Department of Otolaryngology, University of Colorado School of rapidly dividing cancer cells and the surrounding stromal tissue is Medicine, Aurora, Colorado. a critical factor in tumor growth and metastasis, as well as in Corresponding Author: Antonio Jimeno, University of Colorado Cancer Center, treatment efficacy (9). MS8117, 12801 East 17th Avenue, Room L18-8101B, Aurora, CO 80045. Phone: The relationship between the tumor and the stromal immune 303-724-2478; Fax: 303-724-3892; E-mail: [email protected] cells is particularly complex (10). As cancer cells divide, they doi: 10.1158/0008-5472.CAN-16-1260 recruit cells to contribute to the infrastructure of the growing Ó2016 American Association for Cancer Research. tumor, mainly consisting of fibroblasts, endothelial, and www.aacrjournals.org OF1 Downloaded from cancerres.aacrjournals.org on September 30, 2021. © 2016 American Association for Cancer Research. Published OnlineFirst September 1, 2016; DOI: 10.1158/0008-5472.CAN-16-1260 Morton et al. circulating immune cells (11). Although chemokines from the functional lymphocytes. Likewise, during their creation of a breast cancer cells are responsible for the development of the stroma, cancer tumor bank in NOD/SCID mice, DeRose and colleagues signals from the stroma also affect subsequent tumor growth. found that the coimplantation of human mesenchymal stem cells Dysregulated gene expression in the cancer cells results in aberrant (MSC) stimulated angiogenesis throughout the resulting tumors surface antigen presentation that would normally target these cells and promoted their growth (22). These cells can alter the tumor for attack by circulating T cells and NK cells. Cancer cells produce microenvironment, making it temporarily more physiologically cytokines to pacify nearby immune cells and escape immune similar to that found in a cancer patient. surveillance. The chemokine CCL22 can attract T regulatory cells It is becoming increasingly common to create HM by engrafting þ (Treg), which produce cytokines, such as TGFb and IL10, to CD34 human hematopoietic stem and precursor cells (HSPC) downregulate the activity of nearby immune cells. Likewise, many isolated from fetal cord blood or other tissues into the marrow of cytokines, including CCL2, HIF-1a, and VEGF, recruit circulating sublethally irradiated immunocompromised mice to allow them monocytes and myeloid-derived suppressor cells into tumors, to develop into a functional immune system (23). These precursor where they typically differentiate into tumor-associated macro- cells engraft into the damaged bone marrow and, once estab- phages (TAM; ref. 12). Many TAMs quickly convert from an M1 lished, begin to divide into differentiated progeny, including T macrophage anticancer phagocytic phenotype into M2 macro- cells, B cells, macrophages, and other cells capable of interacting phages that suppress immune activity of other cells, leading to a with xenograft tumor tissues. In an early study of this type, Seitz procancer effect. In addition, cancer and/or antigen-presenting and colleagues implanted rhabdomyosarcoma cell lines onto the cells express ligands that inhibit checkpoint receptors in effector flanks of previously humanized NSG mice (24). Tumors origi- immune cells, such as the programmed cell death 1 receptor (PD- nating in the HM were more necrotic, which the authors specu- 1), and cytotoxic T lymphocyte–associated protein 4 (CTLA4). lated may have been due to an interaction with the human Inhibition of these interactions leads to continuous T-cell activa- immune system. Wege and colleagues simultaneously injected tion and has resulted in novel immunotherapies, such as ipilimu- purified HSPCs together with cells from a breast cancer cell line mab (targeting CTLA4), nivolumab (PD-1), and pembrolizumab into the livers of newborn NSG mice (25). Analysis of the mouse (PD-1), which have proven effective as cancer treatments (13). tissues after tumor growth showed evidence of a specific tumor- Because these therapies harness the patients' immune cells to stimulated immune response. HMs have also been used to exam- þ fight their tumors, they rely on the existence of a functional ine leukemia (26). In this case, CD133 cells, thought to be þ human immune system. As such, it has been relatively difficult precursors to even CD34 cells, were injected directly into the to test their effectiveness using conventional experimental mod- bone marrow of NOG (a strain similar to NSG) mice. After els. Early studies examining the efficacy of an anti-CTLA4 immu- evidence of humanization, the mice were injected with human notherapy targeted the murine CTLA4 receptor in mouse fibro- T-cell leukemia virus type I–producing cells and monitored until sarcoma and ovarian cancer models (14). The effectiveness of this they
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