Abstract
Immunotherapy has established itself as a promising tool for cancer treatment. There are many challenges that remain including lack of targets and some patients across various cancers who have not shown robust clinical response. One of the major problems that have hindered the progress in the field is the dearth of appropriate mouse models that can reliably recapitulate the complexity of human immune-microenvironment as well as the malignancy itself. Immunodeficient mice reconstituted with human immune cells offer a unique opportunity to comprehensively evaluate immunotherapeutic strategies. These immunosuppressed and genetically modified mice, with some overexpressing human growth factors, have improved human hematopoietic engraftment as well as created more functional immune cell development in primary and secondary lymphoid tissues in these mice. In addition, several new approaches to modify or to add human niche elements to further humanize these immunodeficient mice have allowed a more precise characterization of human hematopoiesis. These important refinements have opened the possibility to evaluate not only human immune responses to different tumor cells but also to investigate how malignant cells interact with their niche and most importantly to test immunotherapies in a more preclinically relevant setting, which can ultimately lead to better success of these drugs in clinical trials.
Highlights
Specialty section: This article was submitted to Cancer Immunity and Immunotherapy, a section of the journal Frontiers in Immunology
Today it is well established that human HSCs are present within the CD34+CD38−CD90+CD45RA−CD49f+ fraction of the hematopoietic compartment, with an SCID-repopulating cell (SRC) frequency of one in 10 cells [15]
The authors of this work postulated that the expression of human cytokines from the endogenous murine loci, by providing a more physiologic expression of human cytokines, synergistically promotes a more competitive human hematopoiesis including the efficient development of human red blood cell (RBC) and platelets [66]
Summary
HSCs are rare (one in 106 bone marrow cells) undifferentiated multipotent stem cells with the ability to perpetuate themselves for indefinite time through self-renewal. The development of humanized mouse models started with the identification of the severe combined immunodeficient (Scid; mutation in Prkdcscid) mice that lacked B and T cells [22] These mice were shown to allow human T and B cell reconstitution [23]. Human cells that have proven most difficult to generate in these immunodeficient mice have been the erythrocytic and megakaryocytic lineages in which their de novo production from human hematopoietic stem and progenitor cells (HSPCs) normally peaks at 5–7 weeks following the xenotransplantation. Human late-stage immature erythroid cells (CD235a+CD45− nucleated normoblasts) are normally detected in the mouse BM; as these cells reach their maturity to form RBC, they are efficiently eliminated by murine macrophages
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