As one of the most popular laboratory animal models, rodents have been playing crucial roles in mechanistic investigations of oncogenesis as well as anticancer drug or regimen discoveries. However, ...rodent tumors show different or no responses to therapies against human cancers, and thus, in recent years, increased attention has been given to mouse models with xenografted or spontaneous human cancer cells. By combining with the human immune system (HIS) mice, these models have become more sophisticated and robust, enabling
in vivo
exploration of human cancer immunology and immunotherapy. In this review, we summarize the pros and cons of these humanized mouse models, with a focus on their potential as an
in vivo
platform for human cancer research. We also discuss the strategies for further improving these models.
An animal model supporting human erythropoiesis will be highly valuable for assessing the biologic function of human RBCs under physiologic and disease settings, and for evaluating protocols of in ...vitro RBC differentiation. Herein, we analyzed human RBC reconstitution in NOD/SCID or NOD/SCID/γc−/− mice that were transplanted with human CD34+ fetal liver cells and fetal thymic tissue. Although a large number of human CD45−CD71+ nucleated immature erythroid cells were detected in the bone marrow, human RBCs were undetectable in the blood of these mice. Human RBCs became detectable in blood after macrophage depletion but disappeared again after withdrawal of treatment. Furthermore, treatment with human erythropoietin and IL-3 significantly increased human RBC reconstitution in macrophage-depleted, but not control, humanized mice. Significantly more rapid rejection of human RBCs than CD47-deficient mouse RBCs indicates that mechanisms other than insufficient CD47-SIRPα signaling are involved in human RBC xenorejection in mice. All considered, our data demonstrate that human RBCs are highly susceptible to rejection by macrophages in immunodeficient mice. Thus, strategies for preventing human RBC rejection by macrophages are required for using immunodeficient mice as an in vivo model to study human erythropoiesis and RBC function.
Objectives
Immunodeficient mice injected with human cancer cell lines have been used for human oncology studies and anti‐cancer drug trials for several decades. However, rodents are not ideal species ...for modelling human cancer because rodents are physiologically dissimilar to humans. Therefore, anti‐tumour drugs tested effective in rodents have a failure rate of 90% or higher in phase III clinical trials. Pigs are similar to humans in size, anatomy, physiology and drug metabolism rate, rendering them a desirable pre‐clinical animal model for assessing anti‐cancer drugs. However, xenogeneic immune rejection is a major barrier to the use of pigs as hosts for human tumours. Interleukin (IL)‐2 receptor γ (IL2RG), a common signalling subunit for multiple immune cytokines including IL‐2, IL‐4, IL‐7, IL‐9, IL‐15 and IL‐21, is required for proper lymphoid development.
Materials and Methods
IL2RG−/Y pigs were generated by CRISPR/Cas9 technology, and examined for immunodeficiency and ability to support human oncogenesis.
Results
Compared to age‐matched wild‐type pigs, IL2RG−/Y pigs exhibited a severely impaired immune system as shown by lymphopenia, lymphoid organ atrophy, poor immunoglobulin function, and T‐ and NK‐cell deficiency. Human melanoma Mel888 cells generated tumours in IL2RG−/Y pigs but not in wild‐type littermates. The human tumours grew faster in IL2RG−/Y pigs than in nude mice.
Conclusions
Our results indicate that these pigs are promising hosts for modelling human cancer in vivo, which may aid in the discovery and development of anti‐cancer drugs.
Abstract
Background
Blood vessels that contain endothelial cells (ECs) on the surface are in direct contact with host blood and are the first target of xenograft rejection. Currently, our ...understanding of human anti‐pig vessel immune responses is primarily based on in vitro assays using pig ECs. Therefore, it is necessary to develop an animal model that permits in vivo study of human immunological rejection of pig vessels.
Methods
Pig artery tissues (PAT) were transplanted into human immune system (HIS) mice or immunodeficient NSG mice (as controls). Intragraft human immune cell infiltration and antibody deposition were quantified using histology and immunohistochemistry. Donor antigen‐specific immune responses were quantified using a mixed lymphocyte reaction and a complement‐dependent killing assay.
Results
Pig CD31
+
ECs were detected and increased 2‐fold from weeks 3 to 5 in PAT xenografts from immunodeficient NSG mice. However, compared with NSG mice, PAT xenografts in HIS mice had significantly lower numbers of porcine CD31
+
ECs and showed a marked reduction from week 3 to week 5. PAT xenograft rejection in HIS mice is associated with intensive infiltration of human immune cells, deposition of human IgM and IgG antibodies, and the formation of a tertiary lymphoid structure. Robust donor pig antigen‐specific human T cells and antibody responses were detected in PAT‐transplanted HIS mice.
Conclusion
We have developed a humanized mouse model to evaluate human anti‐pig xenoimmune responses by PAT transplantation in vivo. This model is expected to facilitate the refinement of pig gene‐editing strategies (the expression on EC surface) and the testing of local immunosuppressive strategies for clinical pig organ xenotransplantation.
Transgenic CD47 overexpression is an encouraging approach to ameliorating xenograft rejection and alloresponses to pluripotent stem cells, and the efficacy correlates with the level of CD47 ...expression. However, CD47, upon ligation, also transmits signals leading to cell dysfunction or death, raising a concern that overexpressing CD47 could be harmful. Here, we unveiled an alternative source of cell surface CD47. We showed that extracellular vesicles, including exosomes, released from normal or tumor cells overexpressing CD47 (transgenic or native) can induce efficient CD47 cross-dressing on pig or human cells. Like the autogenous CD47, CD47 cross-dressed on cell surfaces is capable of interacting with SIRPα to inhibit phagocytosis. However, ligation of the autogenous, but not cross-dressed, CD47 induced cell death. Thus, CD47 cross-dressing provides an alternative source of cell surface CD47 that may elicit its anti-phagocytic function without transmitting harmful signals to the cells. CD47 cross-dressing also suggests a previously unidentified mechanism for tumor-induced immunosuppression. Our findings should help to further optimize the CD47 transgenic approach that may improve outcomes by minimizing the harmful effects of CD47 overexpression.
Summary
Allogeneic hematopoietic cell transplantation (allo‐HCT) is increasingly being performed to treat patients with hematologic malignancies. However, separating the beneficial graft‐versus‐tumor ...(GVT) or graft‐versus‐leukemia effects from graft‐versus‐host disease (GVHD) has been difficult and remains a significant challenge toward improving therapeutic efficacy and reducing toxicity of allo‐HCT. GVHD is induced by donor T cells that also mediate potent anti‐tumor responses. However, despite the largely shared effector mechanisms, extensive animal studies have demonstrated the potential of dissociating the GVT effect from GVHD. Also in many clinical cases, long‐term remission was achieved following allo‐HCT, without significant GVHD. A better mechanistic understanding of the immunopathophysiology of GVHD and GVT effects may potentially help to improve allo‐HCT as well as maximize the benefit of GVT effects while minimizing GVHD. In this article, we review the role of IFN‐γ in regulation of alloresponses following allo‐HCT, with a focus on the mechanisms of how this cytokine may separate GVHD from GVT effects.
Osteopontin (OPN) is a multifunctional phosphorylated protein. It is widely involved in solid tumor progression, such as intensification of macrophage recruitment, inhibition of T-cell activity, ...aggravation of tumor interstitial fibrosis, promotion of tumor metastasis, chemotherapy resistance, and angiogenesis. Most of these pathologies are affected by tumor-associated macrophages (TAMs), an important component of the tumor microenvironment (TME). TAMs have been extensively characterized, including their subsets, phenotypes, activation status, and functions, and are considered a promising therapeutic target for cancer treatment. This review focuses on the interaction between OPN and TAMs in mediating tumor progression. We discuss the strategies for targeting OPN and TAMs to treat cancer and factors that may affect the therapeutic outcomes of blocking OPN or depleting TAMs. We also discuss the role of cancer cell- vs. TAM-derived OPN in tumorigenesis, the mechanisms of how OPN affects TAM recruitment and polarization, and why OPN could mediate anti-tumor and pro-tumor effects, as well as previously reported discrepancies.
We experimentally investigate the quantum criticality and Tomonaga-Luttinger liquid (TLL) behavior within one-dimensional (1D) ultracold atomic gases. Based on the measured density profiles at ...different temperatures, the universal scaling laws of thermodynamic quantities are observed. The quantum critical regime and the relevant crossover temperatures are determined through the double-peak structure of the specific heat. In the TLL regime, we obtain the Luttinger parameter by probing sound propagation. Furthermore, a characteristic power-law behavior emerges in the measured momentum distributions of the 1D ultracold gas, confirming the existence of the TLL.
Cancer immunotherapy is to artificially stimulate the immune system against tumor cells. Effectively increasing the immunogenicity of dying tumor cells has great potential to stimulate the anticancer ...immune responses. Recently, a synthetic cationic anticancer polypeptide (ACPP) is prepared, which mimics the host defense peptides, to effectively inhibit tumor growth by directly inducing rapid necrosis of cancer cells through a membrane‐lytic mechanism. Thus, this ACPP has the potential ability to induce immunogenic cancer cell death (ICD) and promote antitumor immunity. Herein, it is reported that ACPP successfully induces ICD in mouse colon cancer cells, resulting in effectively promoting T‐cell‐dependent antitumor immune responses by enhanced activation of dendritic cells. Interestingly, the level of natural killer cells, which are another kind of antitumor effector cell, in tumor microenvironment is also significantly increased by ACPP. The ratio of M1/M2 tumor‐associated macrophages is further obviously increased, indicating that tumor immunosuppressive microenvironment has been effectively reprogramed. More importantly, it is found that the anticancer immunity induced by ACPP is dose dependent. Finally, 40% of the established CT26 tumors are completely eliminated by ACPP treatment with an optimized dose. This study proposes a simple and effective strategy for promoting cancer immunotherapy.
The cationic anticancer polypeptide (ACPP) effectively induces immunogenic cancer cell death and promotes antitumor immunity. Intratumorally injected ACPP reprograms the tumor immunosuppressive microenvironment through increasing the frequencies of activated CD8 T cells and natural killer cells. The ACPP with an optimized dose has the potential to eliminate established tumors in CT26 tumor‐bearing mice.
Humanized immune system (HIS) mice have been developed and used as a small surrogate model to study human immune function under normal or disease conditions. Although variations are found between ...models, most HIS mice show robust human T cell responses. However, there has been unsuccessful in constructing HIS mice that produce high-affinity human antibodies, primarily due to defects in terminal B cell differentiation, antibody affinity maturation, and development of primary follicles and germinal centers. In this review, we elaborate on the current knowledge about and previous attempts to improve human B cell development in HIS mice, and propose a potential strategy for constructing HIS mice with improved humoral immunity by transplantation of human follicular dendritic cells (FDCs) to facilitate the development of secondary follicles.
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