Advances in Human Immune System Mouse Models for Personalized Treg-Based Immunotherapies.

Isabelle Serr,Maria Kral,Carolin Daniel,Martin G Scherm

doi:10.3389/fimmu.2021.643544

Abstract

Immunodeficient mice engrafted with a functional human immune system [Human immune system (HIS) mice] have paved the way to major advances for personalized medicine and translation of immune-based therapies. One prerequisite for advancing personalized medicine is modeling the immune system of individuals or disease groups in a preclinical setting. HIS mice engrafted with peripheral blood mononuclear cells have provided fundamental insights in underlying mechanisms guiding immune activation vs. regulation in several diseases including cancer. However, the development of Graft-vs.-host disease restrains relevant long-term studies in HIS mice. Alternatively, engraftment with hematopoietic stem cells (HSCs) enables mimicking different disease stages, however, low frequencies of HSCs in peripheral blood of adults impede engraftment efficacy. One possibility to overcome those limitations is the use of patient-derived induced pluripotent stem cells (iPSCs) reprogrammed into HSCs, a challenging process which has recently seen major advances. Personalized HIS mice bridge research in mice and human diseases thereby facilitating the translation of immunomodulatory therapies. Regulatory T cells (Tregs) are important mediators of immune suppression and thereby contribute to tumor immune evasion, which has made them a central target for cancer immunotherapies. Importantly, studying Tregs in the human immune system in vivo in HIS mice will help to determine requirements for efficient Treg-targeting. In this review article, we discuss advances on personalized HIS models using reprogrammed iPSCs and review the use of HIS mice to study requirements for efficient targeting of human Tregs for personalized cancer immunotherapies.

Highlights

With the discovery of checkpoint inhibitors and more recently, the use of chimeric antigen-receptor T cells, immunotherapies have taken center stage in oncology
In line with highly variable treatment outcomes in patients, two studies did not observe changes in tumorinfiltrating Treg frequencies [11, 38], while one study using a combination of anti-PD-1 antibody and CD137 antibody therapies reported an increase in CD8/Treg ratio in tumors of human immune system (HIS) mice xenotransplanted with gastric carcinoma and engrafted with autologous peripheral blood mononuclear cells (PBMCs) from the same donor [55]
The perpetual improvements of HIS mouse models have enabled the design of personalized immunotherapies for various diseases including cancer and the evaluation of their efficacy prior to the translation to the human setting

Summary

Introduction

With the discovery of checkpoint inhibitors and more recently, the use of chimeric antigen-receptor T cells, immunotherapies have taken center stage in oncology. Especially the potent checkpoint inhibition with anti-PD1 humanized antibodies has been tested in HIS mice bearing various types of tumors [8, 9, 11], highlighting the value of PDX engrafted HIS models for cancer immunotherapies. The potential of personalized HIS mouse models for the analysis of patient specific immune responses was demonstrated in a PDX-bearing HIS mouse model based on NSG mice engrafted with autologous tumor-infiltrating T cells and tumor cells from the same patient.

Results

Conclusion