Date Published: September 19, 2019
Publisher: Public Library of Science
Author(s): Olga Tanaskovic, Maria Vittoria Verga Falzacappa, Pier Giuseppe Pelicci, Chang H. Kim.
Since their appearance, humanized mice carrying human immune system seemed promising tools to study the crosstalk between cancer and immunity. The NOD-scidIL2Rgammanull (NSG) mice engrafted with human cord blood (hCB)-CD34+ cells have been proposed to be a valuable tool to reproduce human immune system in mouse. However, the lack of solid evidences on the functionality of their human immune components limits their usage in immune-oncology. We report that (hCB)-CD34+ cells lose their ability to propagate and originate bone marrow-derived human immune cells after two serial transplantations in NSG mice. We demonstrate that transplants of bone marrow patient-derived acute myeloid leukemias (hAMLs) grow very similarly in the humanized (hCB)-CD34+ NSG and parental NSG mice. The similar extent of engraftment and development of leukemias in (hCB)-CD34+ NSG and controls suggests a poor human immune response against not compatible hAMLs. Our findings suggest that (hCB)-CD34+ NSG mice are transient and/or incomplete carriers of the human immune system and, therefore, represent a suboptimal tool to study the interaction between tumor and immune cells.
In vitro studies are excellent tools to investigate pathways and interactions among few cellular and molecular components, however they do not allow to fully recapitulate complex biological mechanisms that require several cellular and molecular players. For this reason, they are incomplete models to explore the role of the immune system in many complex physiological and pathological conditions. The immune-oncology field aims to study, exploit and manipulate the immunity to recognize and eliminate cancer cells. In order to model the interactions between the human immune system and the human tumoral components, it is necessary to reproduce both in an in vivo context. Human xenografted tumors are well established in vivo model systems, where human cancer cells or tumor biopsies are heterotransplanted into immunodeficient rodents. On the other hand, humanized mice, which carry a human immune system, have been developed over the past three decades[1,2]. The development of humanized mouse models relies on the use of immuno-deficient mice, which allow the engraftment of human hematopoietic stem cells (hHSCs) and tissues, followed by generation of a functional human immunity in the murine context. Over the past years, different immune-deficient mouse strains have been developed and tested for hHSC and tissue engraftment. Many steps forward have been made to obtain a good level of engraftment of the human cells. Initially, CB17-scid mice were shown to support the engraftment of hHSCs only at low level, due to the presence of murine immune barriers (i.e. NK cells). Consecutively, NOD-scid mice allowed good engraftment of hHSCs, but their relatively short life span and residual innate immunity represented considerable limitations. Finally, NOD-scidIL2Rgammanull (NSG) mice, which lack all the components of murine innate immunity and allow a highly efficient engraftment of human HSCs[6,7], became a gold standard to recapitulate the human immune system in mice.
In order to study the interactions between human acute myeloid leukemia (hAML) and human immune system, we developed a humanized NSG mouse model by transplanting human CD34+ ((hCB)-CD34+) cells from the cord blood of healthy donors. Despite the fact that these mice develop impaired human T-cell compartment, due to the lack of human thymus, we aimed to test whether the partial inefficiency of the human immune system in this model could reduce a potential GvH response and allow human tumor growth. Finding a murine humanized system where the incomplete immunological response allows, to a certain degree, tumor growth would be, anyhow, a valuable tool for immuno-oncological studies.