Advances in Human Immune System (HIS) Mouse Models for Studying Human Hematopoiesis and Cancer Immunotherapy

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22 April 2021
Humanized Mouse Models for the Advancement of Innate Lymphoid Cell-Based Cancer Immunotherapies
Nina B. Horowitz
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John B. Sunwoo
Immunotherapies that involve ILC antitumor activity can be categorized as antibody-based, cell-based, or other bioengineered immunomodulators. Mouse models such as PD-1 and CTLA-4 knock-in can be used to study checkpoint inhibitors. SCID mice bearing PDX or CDX can be used to study the efficacy of single agent cell therapies such as CAR NK cells or NK92 cells. HIS mice are the most optimal tool to study combination therapies or immunomodulators that may alter the behavior of multiple immune cell types.

Innate lymphoid cells (ILCs) are a branch of the immune system that consists of diverse circulating and tissue-resident cells, which carry out functions including homeostasis and antitumor immunity. The development and behavior of human natural killer (NK) cells and other ILCs in the context of cancer is still incompletely understood. Since NK cells and Group 1 and 2 ILCs are known to be important for mediating antitumor immune responses, a clearer understanding of these processes is critical for improving cancer treatments and understanding tumor immunology as a whole. Unfortunately, there are some major differences in ILC differentiation and effector function pathways between humans and mice. To this end, mice bearing patient-derived xenografts or human cell line-derived tumors alongside human genes or human immune cells represent an excellent tool for studying these pathways in vivo. Recent advancements in humanized mice enable unparalleled insights into complex tumor-ILC interactions. In this review, we discuss ILC behavior in the context of cancer, the humanized mouse models that are most commonly employed in cancer research and their optimization for studying ILCs, current approaches to manipulating human ILCs for antitumor activity, and the relative utility of various mouse models for the development and assessment of these ILC-related immunotherapies.

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Immunotherapy is a curable treatment for certain cancers, but it is still only effective in a small subset of patients, partly because of the lack of sufficient immune cells in the tumor. It is reported that targeted lactate dehydrogenase (LDH) to reduce lactic acid production can promote the infiltration and activity of immune cells and turn tumors into hot tumors. Therefore, we constructed a humanized mouse model to evaluate the efficacy of using classical LDH inhibitor oxamate and pembrolizumab alone or in combination in non-small cell lung cancer (NSCLC). We found that both oxamate and pembrolizumab monotherapy significantly delayed tumor growth; moreover, combination therapy showed better results. Immunofluorescence analysis showed that oxamate treatment increased the infiltration of activated CD8+ T cells in the tumor, which might have enhanced the therapeutic effects of pembrolizumab. Treatment of the humanized mice with anti-CD8 abrogated the therapeutic effects of oxamate, indicating CD8+ T cells as the main force mediating the effect of oxamate. In conclusion, Our preclinical findings position that oxamate not only inhibits tumor growth at a high safe dose but also enhances the efficacy of pembrolizumab in Hu-PBMC-CDX mice. Our study also provides a preclinical model for exploring the efficacy of other immune-based combination therapies for NSCLC.

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Cancer immunotherapies target the patients own immune system by restoring and stimulating various immune components that ultimately had the potential to inhibit cancer growth and/or eradicate cancer. The various types of immunotherapies that are currently being used in the clinic or are under development include antibody-based immunotherapy, oncolytic virus therapy, cytokine therapy, cellular therapy, cancer vaccines. These therapies are also being used as combination therapies that target multiple immune components or with other established therapeutic options such as chemotherapy.
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Original Research
08 September 2020
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Frontiers in Immunology

Community Series in Immune Responses Against Tumors - From the Bench to the Bedside: Volume II
Edited by Tiezheng Hou, Xiaoxiao Liu, CHUNJING WANG, Shisan (Bob) Bao
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30 May 2025
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